Biomolecular machines

[Pooky]

Teleological.

I thought that we had finally gotten rid of you.

How many nicks do you have here on MyADSL now?

He can have as many as he wants, as long as he continues to confuse me!

 

[Phronesis]

Teleological.

I thought that we had finally gotten rid of you.

How many nicks do you have here on MyADSL now?

Hey nauseous_monkey,

Who are the "we" and what did you do?
I have a few nicks here.
Fearisgood (1st)
Teleological
Isoflavone (or something similar)
Techne
and now this corny one.

 

[cyghost]

I have a few nicks here.
Fearisgood (1st)
Teleological
Isoflavone (or something similar)
Techne
and now this corny one.

I'll take that as evidence that you are not singularity and oxphos. even though they had / have similar styles to you. after all, that would be simply too much!

Okay, okay, I confess, I am secretly w1z4rd, nauseous, claymore and preases

kiddinks!

having only one nick myself and giving the above plethora of nicks, is it any wonder I am paranoid at times?

 

[nauseous_monkey]

Having so many nicks probably gives the illusion of support in your arguments in a thread. It is a bit sad though. I only have 1 nick.

 

[Phronesis]

I'll take that as evidence that you are not singularity and oxphos. even though they had / have similar styles to you. after all, that would be simply too much!

Okay, okay, I confess, I am secretly w1z4rd, nauseous, claymore and preases

kiddinks!

having only one nick myself and giving the above plethora of nicks, is it any wonder I am paranoid at times?

Having so many nicks probably gives the illusion of support in your arguments in a thread. It is a bit sad though. I only have 1 nick.

Response (not here in order to keep it on track)


A few more agents and biomolecular machines .
Protein Compass Guides Amoebas Toward Their Prey

ScienceDaily (Oct. 26, 2008) — Amoebas glide toward their prey with the help of a protein switch that controls a molecular compass, biologists at the University of California, San Diego have discovered.

Their finding, recently detailed in the journal Current Biology, is important because the same molecular switch is shared by humans and other vertebrates to help immune cells locate the sites of infections.

The amoeba Dictyostelium finds bacteria by scent and moves toward its meal by assembling a molecular motor on its leading edge. The active form of a protein called Ras sets off a cascade of signals to start up that motor, but what controlled Ras was unknown.

Richard Firtel, professor of biology along with graduate student Sheng Zhang and postdoctoral fellow Pascale Charest tested seven suspect proteins by disrupting their genes. One called NF1, which matches a human protein, proved critical to chemical navigation.

NF1 turns Ras off. Without this switch mutant amoebas extended false feet called pseudopodia in all directions and wandered aimlessly as Ras flickered on and off at random points on their surfaces. “You have to orient Ras in order to drive your cell in the right direction,” Firtel said.

In contrast, normal amoebas with working versions of NF1 elongate in a single direction and head straight for the most intense concentration of bacterial chemicals, the team reports.

The biochemical components of the system match those found in vertebrate immune cells called neutrophils that hunt down bacterial invaders, suggesting that the switch might be a key navigational control for many types of cells, Firtel said. “The pathway and responses are very similar and so are the molecules.”

The US Public Health Service funded this work.

Agents assemble their equipment in order to hunt down their prey. An intentional plan laid out purposefully in order to manipulate the environment as a means to an end... food.


More equipment capable of manipulating the environment as a means to an end....
New Light Shed On Molecular Machinery Required For Translation Of Histone Crosstalk

ScienceDaily (Dec. 14, 2007) — The Stowers Institute's Shilatifard Lab has published findings that shed light on the molecular machinery required for the translation of histone crosstalk, or communication between histones.

Histones are important components of chromatin, the packing material surrounding chromosomal DNA. Also, histones play an important role in the regulation of gene expression. Histone H3 can be modified by methylation and this modification is an essential part of gene expression.

Several years ago, the Shilatifard Lab identified the first histone H3 lysine 4 (H3K4) methyltransferase, known as COMPASS, in yeast. Soon thereafter, it was established that the MLL protein in humans also existed in a COMPASS-like complex capable of methylating H3K4. In 2002, the Shilatifard Lab reported the existence of the first histone crosstalk between histone H2B monoubiquitination for the regulation of histone methylation by COMPASS.

"We now know that this mode of histone crosstalk is highly conserved from yeast to humans, but until now, its molecular mechanism of action was poorly understood. Jung-Shin Lee, a Postdoctoral Research Associate in my laboratory, was able to demonstrate the molecular machinery required for the translation of this histone crosstalk," said Ali Shilatifard, Ph.D., Investigator and senior author on the paper.

This work demonstrated that the Cps35 subunit of COMPASS is required to translate the crosstalk between H2B monoubiquitination and H3 methylation by COMPASS.

"Given the importance of histone methylation by the MLL complex and leukemia pathogenesis, defining the molecular machinery involved in this process could be highly useful," said Dr. Shilatifard.

 

[Phronesis]

Paley’s Watch?​

Cyanobacteria are one of the organisms with the deepest history, with evidence of their remains dating back possibly to about 3.5 billion years ago. So, what is found in some of these simple cells? CLOCKWORK...

A cyanobacterial circadian clockwork.

Cyanobacteria have become a major model system for analyzing circadian rhythms. The temporal program in this organism enhances fitness in rhythmic environments and is truly global--essentially all genes are regulated by the circadian system. The topology of the chromosome also oscillates and possibly regulates the rhythm of gene expression. The underlying circadian mechanism appears to consist of both a post-translational oscillator (PTO) and a transcriptional/translational feedback loop (TTFL). The PTO can be reconstituted in vitro with three purified proteins (KaiA, KaiB, and KaiC) and ATP. These three core oscillator proteins have been crystallized and structurally determined, the only full-length circadian proteins to be so characterized. The timing of cell division is gated by a circadian checkpoint, but the circadian pacemaker is not influenced by the status of the cell division cycle. This imperturbability may be due to the presence of the PTO that persists under conditions in which metabolism is repressed. Recent biochemical, biophysical, and structural discoveries have brought the cyanobacterial circadian system to the brink of explaining heretofore unexplainable biochemical characteristics of a circadian oscillator: the long time constant, precision, and temperature compensation.

On the structure of:
Structural Insights into a Circadian Oscillator

An endogenous circadian system in cyanobacteria exerts pervasive control over cellular processes, including global gene expression. Indeed, the entire chromosome undergoes daily cycles of topological changes and compaction. The biochemical machinery underlying a circadian oscillator can be reconstituted in vitro with just three cyanobacterial proteins, KaiA, KaiB, and KaiC. These proteins interact to promote conformational changes and phosphorylation events that determine the phase of the in vitro oscillation. The high-resolution structures of these proteins suggest a ratcheting mechanism by which the KaiABC oscillator ticks unidirectionally. This posttranslational oscillator may interact with transcriptional and translational feedback loops to generate the emergent circadian behavior in vivo. The conjunction of structural, biophysical, and biochemical approaches to this system reveals molecular mechanisms of biological timekeeping.

A biological clock with all the cogs and gears. The KaiABC clock is a bona fide dynamically oscillating nanomachine that precess unidirectionally and robustly. Present in one of the most primitive, simple organisms...


More on the nanomachinery that governs DNA processing.
Biologists Discover Motor Protein That Rewinds DNA

ScienceDaily (Nov. 2, 2008) — Two biologists at the University of California, San Diego have discovered the first of a new class of cellular motor proteins that “rewind” sections of the double-stranded DNA molecule that become unwound, like the tangled ribbons from a cassette tape, in “bubbles” that prevent critical genes from being expressed.

“When your DNA gets stuck in the unwound position, your cells are in big trouble, and in humans, that ultimately leads to death” said Jim Kadonaga, a professor of biology at UCSD who headed the study. “What we discovered is the enzyme that fixes this problem.”

The discovery represents the first time scientists have identified a motor protein specifically designed to prevent the accumulation of bubbles of unwound DNA, which occurs when DNA strands become improperly unwound in certain locations along the molecule.

“We knew this particular protein caused this disease before we started the study,” said Kadonaga. “That’s why we investigated it. We just didn’t know what it did.”

What this protein, called HARP for HepA-related protein, did astounded Kadonaga and Timur Yusufzai, a postdoctoral fellow working in his laboratory. The two molecular biologists initially discovered that this motor protein burns energy in the same way as enzymes called helicases and, like helicases, attached to the dividing sections of DNA. But while helicases use their energy to separate two annealed nucleic acid strands—such as two strands of DNA, two strands of RNA or the strands of a RNA-DNA hybrid— the scientists found to their surprise that this protein did the opposite; that is, it rewinds sections of defective DNA and thus seals the two strands together again.

As a consequence, the UCSD biologists termed their new enzyme activity an “annealing helicase.”

“We didn’t even consider the idea of annealing helicases before this study started,” said Kadonaga. “It didn’t occur to us that such enzymes even existed. In fact, we never knew until now what happened to DNA when it got stuck in the unwound position.”

Clocks, motors, nanomachines etc. Superbly intelligent biomolecular machinery making life possible.

 

[Phronesis]

A little about RNA splicing machinery: Possibly the most complex macromolecular machine in the cell​

What is RNA splicing?​

Many human genes (+-94%) contain exons (the DNA sequences that code for amino acids). These exons can be spliced together to form different types of proteins from a single gene.

How is it controlled?​

Extensively and exquisitely controlled.

How common is it in humans?​

Human Genes: Alternative Splicing Far More Common Than Thought

ScienceDaily (Nov. 4, 2008) — Scientists have long known that it's possible for one gene to produce slightly different forms of the same protein by skipping or including certain sequences from the messenger RNA. Now, an MIT team has shown that this phenomenon, known as alternative splicing, is both far more prevalent and varies more between tissues than was previously believed.

Two different forms of the same protein, known as isoforms, can have different, even completely opposite functions. For example, one protein may activate cell death pathways while its close relative promotes cell survival.

The researchers found that the type of isoform produced is often highly tissue-dependent. Certain protein isoforms that are common in heart tissue, for example, might be very rare in brain tissue, so that the alternative exon functions like a molecular switch. Scientists who study splicing have a general idea of how tissue-specificity may be achieved, but they have much less understanding of why isoforms display such tissue specificity, Burge said.

Thus, the same gene can result in different functions, depending on the functionality and control of the RNA splicing machinery.

Is it important?​

Humans And Chimps Differ At Level Of Gene Splicing
Not only do we differ genetically, but the way the genes are processed differ.

What happens if the machinery malfunctions?​

Quality control systems are in place.
RNA Biology Finding Makes Waves By Challenging Current Thinking

ScienceDaily (Jan. 23, 2008) — Case Western Reserve University School of Medicine researcher Kristian E. Baker, Ph.D. challenges molecular biology's established body of evidence and widely-accepted model for nonsense-mediated messenger ribonucleic acid (mRNA) decay with a new study. With her collaborator, Ambro van Hoof, Ph.D. of The University of Texas Health Sciences Center, Baker directly tested the "faux 3' UTR" model and proved it could not explain how cells recognize and destroy deviant mRNA. This landmark discovery will redirect mRNA research and expand opportunities for new discoveries in understanding the cells' ability to protect itself from these potential errors.

In all cells, including human, mRNA is a copy of the information carried by a gene on the DNA. Occasionally, mRNA contains errors that can make the information it carries unusable. Cells posses a remarkable mechanism to detect these aberrant mRNAs and eliminate them from the cell -- this process represents a very important quality control system for gene expression. "A significant amount of past research in this area of RNA biology has collected data to support the 'faux 3' UTR' model for mRNA quality control, and, as a result, has shaped present research directions in the field," said Baker. "Our recent findings preclude this explanation and will, undoubtedly, result in a rethinking by many as to how to experimentally approach this important cellular process."

For decades researchers have been puzzled by cells' ability to differentiate between "normal" mRNA and those carrying certain types of mutations. mRNA transports DNA's genetic coding information to the sites of protein synthesis: ribosomes. Cells are able to identify mRNA carrying a mutation and prevent it from reaching the protein synthesis phase. Once identified, the cell destroys the abnormal, mutated mRNA. This naturally occurring process ensures malfunctioning proteins are not produced.

Using a yeast model system, Baker's research offers a better understanding of this mRNA quality control process which closely mimics the process in human cells.

Present in yeast, primitive organisms

But how prevalent is this kind of machinery?​

Visualizing The Machinery Of mRNA Splicing

ScienceDaily (Apr. 8, 2008) — Recent research at Yale provided a glimpse of the ancient mechanism that helped diversify our genomes; it illuminated a relationship between gene processing in humans and the most primitive organisms by creating the first crystal structure of a crucial self-splicing region of RNA.

This work, published in Science, highlights a 16-year quest by Anna Marie Pyle, the William Edward Gilbert Professor of Molecular Biophysics & Biochemistry at Yale, and her research team into the nature of "group II" introns, a particular type of intron within gene transcripts that catalyzes its own removal during the maturation of RNA.

Group II introns are found throughout nature, in all forms of living organisms. Although much has been learned about their structure and how they work through biochemical and computational analysis, until now there have been no high-resolution crystal structures available. The resulting images have provided both confirmation of the earlier work and new information on the three-dimensional structure of RNA and the mechanism of splicing.

"One of the most exciting aspects of this work was that we did not need to do anything disruptive to these molecules to prepare them for structural analysis," said Pyle. "The molecules showed us their structure, their active site and their activity -- all in a natural state. We were even able to visualize their associated ions."

According to Pyle, the crystal structure revealed some unexpected features -- showing two sections that were most implicated as key elements of the active site and strengthening a theory that the process of splicing in humans "shares a close evolutionary heritage" with ancient forms of bacteria.

Forms of this machinery present all the way down to bacteria .



Here is a video describing the process.

 

[Phronesis]

How 'molecular machines' kick start gene activation revealed

How 'molecular machines' inside cells swing into action to activate genes at different times in a cell's life is revealed today (6 November) in new research published in Molecular Cell. Genes are made of double stranded DNA molecules containing the coded information an organism's cells need to produce proteins. The DNA double strands need to be 'melted out' and separated in order for the code to be accessed. Once accessed, the genetic codes are converted to messenger RNAs (mRNA) which are used to make proteins. Cells need to produce particular proteins at different times in their lives, to help them respond and adapt to changes in their environment.

The "melting out" process is carried out by helicases which is part of the replisome. Exquisitely controlled.
Helicases are also known to be ring-shaped motor proteins, typically hexamers and separate double-stranded DNA into single-stranded templates for the replication machinery. Replication occurs at about 1000 base pairs per second due to the highly efficient combination of sliding clamps and the polymerases. Thus, helicases need to unwind DNA at at least that speed. Unwinding DNA too slowly and the replication machinery might break down . Unwind the DNA too fast or untimely and harmful mutations might occur as single-stranded DNA is prone to degradation and cytosine deamination. The speed at which helicase unwinds DNA is no accident though, as it is intrinsically controlled. As helicase is bound to the lagging strand, it unwinds the leading strand in a separate direction. Applying a pulling force on the leading strand leads to a 7-fold increase in the speed of DNA unwinding by helicase. The highly efficient DNA polymerase/sliding clamp combination provides this controlling force on the leading strand. This forms a robust unwinding/polymerization interaction whereby polymerization controls and prevents unwanted DNA unwinding.

The new study outlines exactly how a molecular machine called RNA polymerase, which reads the DNA code and synthesizes mRNA, is kickstarted by specialised activator proteins. The scientists have discovered that RNA polymerase uses a tightly regulated internal blocking system that prevents genes from being activated when they are not needed.

Using electron microscopy to look at the inner workings of bacterial cells, the researchers discovered that the DNA strand-separating process is kickstarted when RNA polymerase is modified by an activator protein, which the cell sends to the site of the gene that needs to be switched on.

This activator protein jump-starts the RNA polymerase machine by removing a plug which blocks the DNA's entrance to the machine. The activator protein also causes the DNA strands to shift position so that the DNA lines up with the entrance to the RNA polymerase. Once these two movements have occurred and the DNA strands are in position, the RNA polymerase machine gets to work melting them out, so that the information they contain can be processed to produce mRNA, and ultimately allow production of proteins.

Professor Xiaodong Zhang, lead author of the paper from the Department of Life Sciences at Imperial College London, explains the significance of the team's findings, saying:

"Understanding how the RNA polymerase gene transcription 'machine' is activated, and how it is stalled from working when it is not needed, gives us a better insight than ever before into the inner workings of cells, and the complex processes that occur to facilitate the carefully regulated production of proteins."

Professor Martin Buck, Head of Imperial's Division of Biology and one of the paper's co-authors, adds that understanding how this process works in bacteria cells is of particular interest, because it is this gene transcription and protein production process which allows bacterial cells to adapt, respond and thrive despite changes in their environment:

"In other words, this is the process that occurs inside bacteria that makes them so good at survival. Many bacteria cause infection and disease in humans, and are hard to defeat. Bacterial RNA polymerase is a proven target for antibiotics such as rifampicin, against which many bacteria have become resistant. Insights gained form our research will now provide opportunities and strategies for the design of novel antibacterial compounds," he concludes

So machines govern the activity of gene expression, and machines are governed by gene expression through a reasonably optimal genetic code mmmm....

 

[Phronesis]

How Cells Take Out The Trash To Prevent Disease

ScienceDaily (Nov. 10, 2008) — Garbage collectors are important for removing trash; without them waste accumulates and can quickly become a health hazard. Similarly, individual cells that make up such biological organisms as humans also have sophisticated methods for managing waste.

The researchers, including postdoctoral fellows Jason MacGurn and Chris Stefan, identified nine related proteins in yeast, which they named the "arrestin-related trafficking" adaptors or ARTs. Each of these proteins identifies and binds to a different set of membrane proteins. Once bound, the ART protein links to an enzyme that attaches a chemical tag for that protein's removal. The ARTs are found in both yeast and humans, suggesting the fundamental nature of their function.

Once the protein is tagged, the piece of membrane with the targeted protein forms a packet, called a vesicle, that enters the cell's cytoplasm. There, the vesicle enters a larger membrane body called an endosome, which in turn dumps it into another compartment called the lysosome, where special enzymes break apart big molecules to their core units: proteins to amino acids, membranes to fatty acids, carbohydrates to sugars and nucleic acids to nucleotides, and those basic materials are then reused.

The paper in Developmental Cell, co-authored by Emr with postdoctoral fellows David Teis and Suraj Saksena, describes for the first time how a set of four proteins assemble into a highly ordered complex. This complex encircles membrane proteins that must be disposed of in the lysosome. Emr's lab was the first to identify and characterize these protein complexes (known as ESCRTs). The Developmental Cell paper describes the order of events in which the ESCRT complexes encircle and deliver "waste" proteins into vesicles destined for recycling in the lysosome.

Lysosomal, autophagic, chaperone mediated autophagy processes...etc. taking out the trash: All highly regulated, exquisitely controlled processes carried out by biomolecular machines . And these same processes are so ancient... present in yeast...

 

[Phronesis]

How long will a reaction take to complete without enzymes?
Well, some reactions will only complete in about 2.3 billion years without them...
Without Enzyme, Biological Reaction Essential To Life Takes 2.3 Billion Years

But enzymes don't just pop into existence, not even under the BEST pre-biotic synthesis scenarios. Enzymes are produced and folded into the correct conformation by.... other enzymes... controlled by.... biomolecular machines and a genetic code...

 

[Geriatrix]

Phronesis, I was wondering. What do you do for a living?
I'm just interested because you seem to have a lot of free time to read, research and post these articels(which are, don't get me wrong, very interesting). Also, your interest in the inner workings of cells and biomechemical processes seem to be much more developed than regular science buffs. The teleological undertone in your posts also makes me wonder what drives your interest and motivation.

Btw I'm not attacking you or anything I am genuinely just interested. As you might have guessed from the pattern of my posts and responses to posts I'm more interested in how people think and what drives them than any indication of how it relates to my personal religious or secular motivations.

 

[nauseous_monkey]

Teleological is in the boredom business. And he is making billions.

 

[Phronesis]

Geriatrix,

Don't worry too much about what I do for a living . Anonymity allows for an argument to be scrutinized rather than the person. What drives my interest? Well, it is there, I find it interesting. From experience, you don't seem like a "threaty" person, so I did not expect it to be a personal attack. I too am interested in other people's motivations for acting.

More about the efficiency of enzymes:
Biochemistry: Enzymes under the nanoscope

Small-scale interactions of substrates with an enzyme's active site — over distances smaller than the length of a chemical bond — can make big differences to the enzyme's catalytic efficiency.

When Richard Feynman died in 1988, he left behind the following words on his blackboard: "What I cannot create, I do not understand." His message certainly resonates with protein engineers.

Enzymes are guided into their correct 3D configuration by other enzyme complexes known as chaperones (part of the heat-shock protein family). What happens if the configurations are not right? Scientists determined that some enzymes, as in the case of ketosteroid isomerase, are so precisely folded for their particular ligand/substrate that if it the 3d conformation was off by even 10 picometers (10^12 meters) it would lose its efficiency. Firstly, the conformation has to be just right to tightly bind the ligand into the pocket of the protein, then another mechanism (built in property of the enzyme) is responsible the transfer of electrons in order to catalyze and complete the enzymatic reaction. Our current best efforts at designing artificial enzymes are (from the article) “still tens of billions of times smaller than those of many enzymes.”

The ribosome is a super complex of enzymes, a molecular machine responsible for the building of polypeptide chains which in turn are folded into active proteins by chaperone complexes.
Problems do occur, but checks and balances are present. For example:
Side-chain recognition and gating in the ribosome exit tunnel
At the exit tunnel of the ribosome, it is hypothesized that there are gate and latch mechanisms with active valves controlling the exit of polypeptides. The researchers conclude that these mechanisms play a role in the regulation of "nascent chain exit and ion flux". Sort-off like a final checkpoint.

 

[Phronesis]

As already seen, without enzymes, reactions that are crucial to life might take billions of years to complete. Small changes (10 picometers) in the 3D structure of an enzyme can also negatively affect the function of an enzyme.
So how are enzymes folded into their active conformation?

Chaperonins: Two-stroke, two-speed, protein machines

Article:
Setting the chaperonin timer: A two-stroke, two-speed, protein machine
From the article:

Protein machines and their man-made, macroscopic counterparts share several common attributes, e.g., concerted, coordinated movements, cyclical operation, and energy transduction. These machines are seldom reversible because each cycle generally involves at least one irreversible step, e.g., the consumption of fuel. Often these machines operate at variable speed, a plethora of timing devices adjusting the cycle speed in response to demand.

An exemplary bipartite protein machine is the chaperonin system, typified by GroEL and GroES from Escherichia coli. GroEL is composed of 2 heptameric rings, stacked back to back, which, in the presence of GroES, operate out of phase with one another in the manner of a 2-stroke, reciprocating motor (1, 2). Driven by the hydrolysis of ATP, the chaperonin proteins function as a biological simulated annealing machine (3, 4), optimizing the folding of their substrate proteins (SPs) whose passage to biologically functional conformations is thus assured.

The picture of the chaperonins that emerges from our work is that of a machine equipped with a timer, the trans ring, poised to respond to the appearance of SP [substrate protein inside the cavity] but otherwise idling in a quiescent state. We note that Nature’s design of this 2-speed protein machine minimizes the hydrolysis of ATP in the absence of SP. However, it maximizes the number of turnovers and minimizes the residence time available to the encapsulated SP to reach the native state, design principles well suited to the operation of an iterative annealing device.

Partial part and dynamics of the system.
Nice video of how it operates

Machines folding machines into place. Beautiful...

 

[Geriatrix]

Geriatrix,

Don't worry too much about what I do for a living . Anonymity allows for an argument to be scrutinized rather than the person. What drives my interest? Well, it is there, I find it interesting. From experience, you don't seem like a "threaty" person, so I did not expect it to be a personal attack. I too am interested in other people's motivations for acting.

Yes I understand the need for anonymity(there are some colourfull people on this site ), I was just wondering if its a career related interest or just personal. I just realised that that may have been a bit of a personal question, sorry mate, I should have PM'd.

Anywhoo, as you were...

 

[Phronesis]

Yes I understand the need for anonymity(there are some colourfull people on this site ), I was just wondering if its a career related interest or just personal. I just realised that that may have been a bit of a personal question, sorry mate, I should have PM'd.

Anywhoo, as you were...

No worries, no problem .

More on protein folding:
Many proteins have intricate folds and one of these fold types include the figure eight knot fold. A team of researchers tried to figure out how these proteins are folded. At present, it is only known that the knot is formed quickly soon after polypeptide chain formation, with an unknown mechanism. The researchers tentatively propose:
"an early threading event may be the defining feature of a polypeptide-knotting with the ensuing folding occurring in a similar fashion to unknotted proteins; the folding of a knotted protein differs only with an initial knotting event in a denatured-like state."

Perhaps an an as of yet undiscovered knot-folding machine?
Article: Exploring knotting mechanisms in protein folding


And nanotubes? Bah, old news... a few hundred million years old...
Tunnelling nanotubes: Life's secret network

The closest animal equivalents to plasmodesmata were thought to be gap junctions, which are like hollow rivets joining the membranes of adjacent cells. A channel through the middle of each gap junction directly connects the cell interiors, but the channel is very narrow - just 0.5 to 2 nanometres wide - and so only allows ions and small molecules to pass from one cell to another.

Nanotubes are something different. They are 50 to 200 nanometres thick, which is more than wide enough to allow proteins to pass through. What's more, they can span distances of several cell diameters, wiggling around obstacles to connect the insides of two cells some distance apart. "This gives the organism a new way to communicate very selectively over long range," says Gerdes. It is a previously unknown way in which cells can communicate over a distance

Soon after they first saw nanotubes in rat cells, he and Rustom saw them forming between human kidney cells too. Using video microscopy, they watched adjacent cells reach out to each other with antenna-like projections, establish contact and then build the tubular connections. The connections were not just between pairs of cells. Cells can send out several nanotubes, forming an intricate and transient network of linked cells lasting anything from minutes to hours. Using fluorescent proteins, the team also discovered that relatively large cellular structures, or organelles, could move from one cell to another through the nanotubes

Their work, published in May, shows that nanotubes are not just an artefact of the methods used to grow cells in culture, as some have suggested. And what they have seen is spectacular: some of the longest tunnelling nanotubes ever observed, more than 300 micrometres long, connecting dendritic cells in the cornea (The Journal of Immunology, vol 180, p 5779). "We can see them their whole course, spindling all the way through the cornea," says McMenamin. "It's fantastic."

"I'll bet you that within weeks to months, people will start noticing them in other tissues. It's just a case of how you look," he adds. "You've got to know what you are looking for. It's a bit like being a good bird-watcher. A hundred people will see a flock of seagulls, and it's only a very good bird-watcher who will spot this one tern flying in that flock."

Gerdes, meanwhile, continues to marvel at what is unravelling before his very eyes. "Whatever one can think of has been done by nature," he says. "It is unbelievable what the cell is able to do."

One striking feature that makes us different from other primates is our innate ability to develop a theory of mind at around 4-6 years. We start to develop the remarkable ability to simulate what other people are thinking and understand their thoughts through our own thinking. We also create our own model of the world in our own minds that leads to understanding of concepts.

Attempting to unravel nature's mysteries by trying to look at it from another engineering Mind's eye seems to make sense when one marvels at the engineering feats in cells. Why not?

 

[Phronesis]

Article related to the unique operations of biological molecular machines
Fluctuation as a tool of biological molecular machines
Abstract:

The mechanism for biological molecular machines is different from that of man-made ones. Recently single molecule measurements and other
experiments have revealed unique operations where biological molecular machines exploit thermal fluctuation in response to small inputs of energy
or signals to achieve their function. Understanding and applying this mechanism to engineering offers new artificial machine designs.

The article continues:

Biological machines are different from man-made artificial ones in many ways. One primary difference is the amount of energy supplied. For example, a supercomputer playing chess with a champion uses much larger amounts of energy than its adversary. A computer unit element, or IC chip, uses energy much larger than thermal energy (500 times greater) to avoid the disturbance caused from thermal noises whereas biological machines use the energy released from the hydrolysis of ATP, which is only approximately 10 times greater than thermal energy. Large excess energy inputs in computers result in far less efficiency at converting their energy inputs although they are more precise at their task than biological machines. Computers err once per 1060 trials, while basic biochemical reactions underlying biological machines err as often as once per 103 trials. For this reason, computers are in some respects superior to one of nature’s greatest machines, the human brain. Computers make calculations much faster as IC chips work on the order of nanoseconds (10−9 s), while the time scale for basic biochemical reactions in biological machines is milliseconds (10−3 s). They also have superior memory capacity and data transfer rate. The computer rate is on the order of 109 bites/s while in brain it is estimated to be only 400 bites/s. However, biological machines are more flexible, readily responding to changes in their environment. In contrast, man-made machines are designed to maintain their. function regardless of environmental changes. Therefore, the fundamental mechanisms between the two machines are different. Biomolecules and their assemblies, biomolecular machines, are in the order of nanometer in size meaning the effects of thermal noises are large. Nevertheless, biomolecules and molecular machines execute their roles despite these noises. But how? Recent experimental data suggest that biological molecular machines harness thermal fluctuation to achieve their functions. Thus, thermal fluctuation seems to play an important role from the molecular level to cellular and organism level. We have developed measurement systems that trace these thermal fluctuations in biomolecular machines when eliminating measurement noise.

Our model biomolecular machine of choice is the molecular motor. Molecular motors are composed of a motor protein, which move using the chemical energy of ATP, and protein tracks, which the motors move along. Molecular motors and protein tracks share unique characteristic properties such as enzymatic activity, molecular recognition, energy conversion and self-organization with other typical molecular machines. Thus the results obtained for molecular motors may be extended to other systems.

Thermal fluctuation is involved in function at different hierarchies of biological systems (Fig. 3). In the mechanism for molecular motor motility, it has been shown that thermal fluctuation is involved and biased to generate directional movement. In live cells, a mechanism that utilizes thermal fluctuation is also likely.

Lastly, in addition to the stochastic nature at the molecular and cellular levels, visual perception has shown stochastic dynamics. Visual perception processes are explained by equations similar to formulae that govern the behavior of biomolecules (Murata et al., 2003). Thus the mechanisms obtained at molecular and cellular levels likely apply at even higher levels. These mechanisms offer blueprints to engineer artificial machines that utilize fluctuations.

Again, showing the carbon based nanotechnology in cells can be utilized and adopted by our engineers for our own designs seeing that these machines are able to harness even thermal fluctuations.

 

[Phronesis]

How DNA Is Unwound So That Its Code Can Be Read

ScienceDaily (Nov. 24, 2008) — Researchers at The Scripps Research Institute have figured out how a macromolecular machine is able to unwind the long and twisted tangles of DNA within a cell's nucleus so that genetic information can be "read" and used to direct the synthesis of proteins, which have many specific functions in the body.

"This is a fundamental processes that takes place countless times inside each of our cells every day, but how it happens had not been understood." says the study's lead investigator, Francisco Asturias, Ph.D., associate professor in the Department of Cell Biology at Scripps Research. "The structure we have solved provides important clues into one of the first steps in gene expression regulation."

Anybody interested in some of the 3D-structure, go to rcsb.org.

"Remarkable Unpacking and Repacking"

To understand the complexity of the process, it is important to know that if the DNA in each cell were stretched out, it would be more than three feet long—and given the trillions of cells within a human body, it has been calculated that a single individual's DNA could stretch to cover the distance to the sun and back many times over.

So DNA must be packaged into tidy little chromosomes. The DNA in each gene first assembles into what looks like a string of beads: the string is the DNA and to compact its length, it is wrapped two times around a spool-like bead of histone protein, to form a nucleosome. But there is so much DNA in a single gene that each gene is packed into a necklace of nucleosomes on a DNA string. These beads then become further compressed into twisted ropes that eventually form chromatin, in which DNA is compacted about 10,000 times from its extended length.

What the Scripps Research scientists set out to do is to understand how the RSC complex unwinds DNA from the many histone beads within a gene so that other molecular machines can read the genetic code.

RSC is a huge complex of 13 different proteins and the scientists first found that it holds an individual nucleosome in what looks like a vise grip. They then found that RSC creates a little bulge in the DNA that can be propagated around the nucleosome and make possible translocation of the DNA with respect to the histones, exposing the DNA so that it can be read.

"Imagine a rubber band wrapped twice around a water glass. The easiest way to move the band is to pull a little of it away from the glass and then slide it" Asturias says. "By using energy from an external source (ATP hydrolysis) RSC can repeatedly pull DNA away from the histones and eventually expose all of the DNA."

The researchers believe that by translocating a nucleosome along the DNA, RSC eventually slides into the next adjoining nucleosome, causing the histones to be ejected and exposing the DNA. "Interestingly, although its DNA is gradually exposed, the nucleosome to which RSC is bound remains intact," Asturias says.

The structure RSC interacting with a nucleosome explains how previously observed DNA bulges formed by chromatin remodeling complexes are formed, and why a single intact nucleosome appears to be left on a fully activated gene before other cellular machinery scoop up the histones and repack the DNA until it needs to be read again.

"Every time your cell expresses a gene, it goes through this remarkable unpacking and repacking," he says. "We are happy to have provided some clarity to the process."

Published article:
Structure of a RSC–nucleosome complex and insights into chromatin remodeling

Nice video showing DNA wrapping.

An interesting blog entry (and an interesting blog worth a read) describes how the transcription machinery is assembled and disassembled in a few sites in cells.

Yet another twist in the world of gene expression - transcription factories

First of all I will ask you, did you know that transcription only happened at a few sites within the nucleus? In mouse cells from the animal there are between 100-300 of these but in cultured cells such as HeLa cells there are many more. Transcription factories also known as RNAPII foci are where most, if not all mRNA is produced. This amazed me and raises the obvious questions of why and how. The why may be obvious. It is a good idea to keep the nucleus as I see it ‘tidy’ but in more technical terms it is a way of keeps gene expression organised and regulating it (see below). The how this work I don’t think has been addressed! All I can say is watch this space.

There is more there.

 

[Claymore]

Does anyone actually read this stuff? It seems to be rather boring; maybe it would be better posted on a blog or in a scientific forum.

 

[nauseous_monkey]

Does anyone actually read this stuff? It seems to be rather boring; maybe it would be better posted on a blog or in a scientific forum.

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