Biomolecular machines

Protein Folding

Nature’s Origami: Protein Folding Is 'Hit And Miss' Process
ScienceDaily (Mar. 11, 2009) — Sometimes known as “nature’s origami”, the way that proteins fold is vital to ensuring they function correctly. But researchers at the University of Leeds have discovered this is a ‘hit and miss’ process, with proteins potentially folding wrongly many times before they form the correct structure for their intended purpose.
Intended purpose? Mmm, this guy should really beware of materialists, this might be mistaken for religious propaganda.
Anyway, as proteins are released from the ribosomal machinery, the amino acid string can fold into various shapes, some causing disease even. So it is is not a case of making the amino acid string and the protein will magically self-organize into the right 3D-configuration. No, several other proteins (e.g. heat shock proteins - HSPs) guide amino acid strings into their correct configuration. It often happens that these HSPs become deficient, and this results in incorrectly folding proteins and disease.

From the article:
The body’s proteins carry out numerous functions and play a crucial role in the growth, repair and workings of cells. Sheena Radford, Professor of Structural Molecular Biology at the University of Leeds, says: “There’s a fine balance between a protein folding into the correct shape so that it can carry out its job efficiently and it folding incorrectly, which can lead to disease. Just one wrong step can tip that balance.”

Proteins are made of amino acids arranged in a linear chain and the sequence of these amino acids is determined by the gene producing them. How these chains of amino acids are preprogrammed to fold into their correct protein structure is one of the mysteries of life.

The culmination of many years’ work, the collaborative study looked at the Im7 protein, a simple protein which is present in bacteria and has a crucial role to play in ensuring that bacteria do not kill themselves with the toxins they produce.

“Im7 is like an anti-suicide agent,” says Professor Radford. “We studied it partly because of its simplicity and partly because of the known evolutionary pressure on the protein to fold correctly to enable the bacteria to survive.”

The study has revealed that these proteins misfold en route to their intended structure, and importantly, has shown the forces at work during the folding process. While the chain of amino acids determines which shape a protein needs to take, the researchers discovered that it was the very amino acids central to the protein’s function that were causing the misfolding.

“This breakthrough could have huge implications for understanding the evolution of today’s protein sequences and in determining the balance between heath and disease,” says Professor Radford. “It’s fundamental science, but significant for our understanding of the mechanisms at work in the human body.”

This research was funded by the Biotechnology and Biological Sciences Research Council, with further support from various organisations including EMBO, the Leverhulme Trust, the Royal Society, and the Medical Research Council. The study was carried out in collaboration with scientists at the University of Cambridge, and the University of Leeds’ School of Physics and Astronomy.

Video of protein folding.
To give an example, consider the following:
Protein folding and degradation in bacteria: to degrade or not to degrade? That is the question.
In Escherichia coli protein quality control is carried out by a protein network, comprising chaperones and proteases. Central to this network are two protein families, the AAA+ and the Hsp70 family. The major Hsp70 chaperone. DnaK, efficiently prevents protein aggregation and supports the refolding of damaged proteins. In a special case, DnaK, together with the assistance of the AAA+ protein ClpB, can also refold aggregated proteins. Other Hsp70 systems have more specialized functions in the cell, for instance HscA appears to be involved in the assembly of Fe/S proteins. In contrast to ClpB, many AAA+ proteins associate with a peptidase to form proteolytic machines which remove irreversibly damaged proteins from the cellular pool. The AAA+ component of these proteolytic machines drives protein degradation. They are required not only for recognition of the substrate but also for substrate unfolding and translocation into the proteolytic chamber. In many cases, specific adaptor proteins modify the substrate binding properties of AAA+ proteins. While chaperones and proteases do not appear to directly cooperate with each other, both systems appear to be necessary for proper functioning of the cell and can, at least in part, substitute for one another.

So even if proteins misfold, other quality control measures are at play to refold and prevent misfolding. When these mechanisms fail, cell death often follows.
Cells have their very own built-in natural selection system.
 
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Oh dear, some confusion here.
Mmm, you see that as well? I did mention natural selection systems and how the mechanisms in the system select FOR functional proteins through various error checking pathways and mechanisms. Perhaps the "natural" and "system" was a bit confusing for some :rolleyes:. Natural selection onits own DOES NOTHING. It does not select FOR anything. Well spotted ;).
 
Mmm, you see that as well? I did mention natural selection systems and how the mechanisms in the system select FOR functional proteins through various error checking pathways and mechanisms. Perhaps the "natural" and "system" was a bit confusing for some :rolleyes:. Natural selection onits own DOES NOTHING. It does not select FOR anything. Well spotted ;).

Dodge duck dive.

Repeat rinse.
 
Dodge duck dive.

Repeat rinse.

It's a bit like this one - y'know, changing out definitions when we get cornered LOL! -

The ill-defined TelePhronetic "intentionality" might be limited to humans, but what about "nana-intentionality" as exhibited by bananas; "front-loader-intentionality" as you find in caterpillars and komatsu-bugs; "flea-bitten intentionality" in domesticated mammals; "forkol-intentionality" in rocks and stones; etc.

Y'see, there are lots of OTHER intentionalities, that aren't intentionality per se, but are intentionality, actually, or maybe not, in fact one cannot reely be sure!
:D:eek:;)

Telephronetic "natural selection" of course DOES NOTHING. But what about "natural selection pizza toppings" that intentionally choose your favourite toppings; "natural selection obelisks" that transport themselves from quarries to places of display; "natural selection hoomans" who, like Stalin, kill off millions to cleanse the gene-pool; and "forkol natural selection" found in rocks, stones, etc ( hey, Katrina? ).

Y'see, there are lots of OTHER "natural selections", which DO THINGS, actually, or maybe not, in fact one cannot reely be sure!
:D:eek:;)
 
Lol rwenzori, try and say something serious you old joker...
Make an argument, make a point, say something constructive.
Here is a thought, why don't you actually make a thread were you make an argument is not out of ignorance and one that does not betray your credulity. And in the process actually answer just a few questions posed to you.... just a few. Truthfully without being snarky... you can do it... ROFL
 
Don't Stress! Bacterial Cell's 'Crisis Command Center' Revealed
ScienceDaily (Oct. 3, 2008) — A bacteria cell's 'crisis command centre' has been observed for the first time swinging into action to protect the cell from external stress and danger, according to new research published in Science

The research team behind the new study says that finding out exactly how bacteria respond and adapt to stresses and dangers is important because it will further their understanding of the basic survival mechanisms of some of the most resilient, hardy organisms on Earth.

The crisis command centre in certain bacteria cells is a large molecule, dubbed a 'stressosome' by the scientists behind today's research. These cells have around 20 stressosomes floating around inside them, and although scientists knew they played an important role in the cell's response to stressful situations, the complexities of this process had not been fully understood until now.

If a bacteria cell finds itself in a dangerous situation - for example, if the temperature or saltiness of the bacteria's environment reach dangerous levels which threaten the survival of the bacteria -a warning signal from the cell's surface is transmitted into the cell.

Using cutting edge electron microscopy imaging techniques the authors of the new research observed that the stressosomes receive this warning signal, and in response several proteins called RSBT break away from the large stressosome. This breakaway triggers a cascade of signals within the cell which results in over 150 proteins being produced - proteins which enable the cell to adapt, react and survive in its new environment.

Professor Marin van Heel from Imperial College London's Department of Life Sciences, one of the corresponding authors of the study, explains: "The cascade of events inside bacteria cells that occurs as a result of stressosomes receiving warning signals leads to particular genes inside the cell being transcribed more. This means that some genes already active inside the cell are 'turned up' so that levels of particular proteins in the cell increase. These changes to the protein make-up of the cell enable it to survive in a hostile or challenging environment."

Dr Jon Marles-Wright from Newcastle University says: "Our work shows that cells respond to signals much like a dimmer on a light switch. Now we'll be building on this to work out how nature controls that dimmer switch. We wouldn't have been able to carry out this work without access to the Diamond synchrotron Light Source which has enabled us to examine the structures of individual stressosome proteins at atomic resolution."

Dr Tim Grant, one of Imperial's post doctoral researchers, adds that the key to bacteria cells' success at surviving in rapidly changing environments is their speedy response: "The cell's stressosomes are very good at their job as crisis command centres because they provide a very fast effective response to danger. The chain reaction they kickstart produces results really quickly which enables bacteria to adapt to changes in their surroundings almost instantaneously."

The team is now planning to collect very high resolution data of the stressosome complex on the world's newest high-resolution cryo electron microscope, the FEI "KRIOS" that has just been installed in the Max Planck Institute in Martinsried, Germany. Improving the resolution of the stressosome structure by a factor of two will lead to a resolution range normally only attainable by X-ray crystallography and will allow the researchers to directly see the amino-acid components of this fascinating complex.

This study has been carried out as a collaboration with the research groups of Professor Rick Lewis at Newcastle University and Professor Marin van Heel from Imperial College London.

Bacteria are examples of minimal molecular autonomous agents occurring in nature. Bacterial cells adapt towards new environments and the process is controlled by stressosomes.
 
The disgusting behaviour of the OP and the subsequent arguments that proves his religious agenda behooves me to implore the powers that be to remove this blight on the face of science from the science sub forum and to discard it to the nether depth of the PD section.

Science has only been kind to us. Should we not return the favour?
 
The disgusting behaviour of the OP and the subsequent arguments that proves his religious agenda behooves me to implore the powers that be to remove this blight on the face of science from the science sub forum and to discard it to the nether depth of the PD section.

Science has only been kind to us. Should we not return the favour?
More drunken rambling ROFL. Must have been a tough week hey?
 
More drunken rambling ROFL. Must have been a tough week hey?

it was. and so with pleasure I bid you, my nemesis, a fond congratulations.

Dragging this down to your level is all that is left for you. that says quite a lot in my esteemed opinion.

I shall continue to argue, if not well, passionately and if all that is left for you is this, then sadly, once again, you have given me victory without much of a battle.
 
The disgusting behaviour of the OP and the subsequent arguments that proves his religious agenda behooves me to implore the powers that be to remove this blight on the face of science from the science sub forum and to discard it to the nether depth of the PD section.

Science has only been kind to us. Should we not return the favour?

We should.

Might I be so bold as to direct the lurking moderators to this post:

http://mybroadband.co.za/vb/showpost.php?p=2590594&postcount=1

Specifically, this bit:

When cells are described as "astonishingly complex molecular machines", it is generally by breathless supporters of ID who take the metaphor literally and assume that such a "machine" requires an "engineer".

To paraphrase the song, I dunno what it is, but it ain't science!
 
Back to posting about interesting findings regarding biomolecular machines:
Cells Get Two Chances, Not Just One, To Fix Their Mistakes
ScienceDaily (Mar. 12, 2009) — Cells have two chances to fix the same mistake in their protein-making process instead of just one – a so-called proofreading step – that had previously been identified, according to new research.

Proteins are essential to life and do most of the work in cells, so avoiding mistakes during their production is a critical way to prevent a variety of harmful conditions that result when mutations cause damage or when cells die.

Better knowledge of the mechanism behind these occasional mistakes could increase understanding of various disease processes, especially in neurodegenerative disorders, some of which scientists suspect are associated with mutated proteins, Ohio State University researchers say.

The discovery of this second step also gives drug-makers a new target to consider, especially in the development of antibiotics. Drugs designed to interfere with the enzymes that make, find and repair the mistakes during protein production could be powerful agents in stopping bacterial cell growth.

One key enzyme involved in cell quality control is called phenylalanyl-tRNA synthetase (PheRS). This enzyme’s job within the cell is to correctly select one of the amino acids that will be strung together into a molecule to make a protein.

“We’re describing a pretty simple process where the cell says, ‘I think I’ll have one more look at that,’” said Michael Ibba, senior author of the study and an associate professor of microbiology at Ohio State. “It looks at the building blocks and checks that they’re right before it makes the protein.”

The research is published in the March 13 issue of the journal Molecular Cell.

In past examinations of this mechanism in the cell, Ibba’s lab had identified a single quality-control measure cells take as they produce proteins. The researchers initially thought that this proofreading step was the only check during the protein-making process.

“There was a step at which we thought, now it’s done, and if a mistake gets through here, it’s irreversible and is going to end up as a mistake. But it turns out there is yet another step at which the cell has another look. It’s checking itself,” Ibba said. “The bottom line is we must have been missing something.”

Previous research has suggested that cells, on average, make one error during protein production for every 10,000 amino acids strung together.

“What we do is try to find out where that error rate number comes from,” said Ibba, also an investigator in Ohio State’s Biochemistry Program and its Center for RNA Biology. “Understanding where the mistakes come from means you can try to predict conditions that will either raise or lower the frequency of mistakes.”

Within the cell, PheRS is one member of a family of enzymes responsible for selecting amino acids that will be attached to an adapter molecule that facilitates the protein-building process. The amino acids must be attached to the appropriate adapter to ensure the genetic code is deciphered properly.

Ibba’s lab has been studying this enzyme’s activities for years. After observing over time what appeared to be a second quality-control step, the scientists had to devise a method they could use to prove the second step occurred. So the researchers first generated the mistake synthetically, and then introduced other enzymes that would normally be present later in protein production to see if they could then observe the second quality check.

The researchers discovered that the same enzyme that makes the mistake, PheRS, also checks and cleans up after itself in a process that removes the incorrect amino acid and attaches the correct one in its place. And the enzyme can do this even after an initial check misses the mistake and allows the protein-building process to continue.

“The enzyme is two catalysts, one that can make the mistake and one that can correct the mistake. It can let the mistake go and grab it back. Nothing tells it to do this. It figures it out on its own,” Ibba said.

These experiments were conducted using E. coli bacterial cells, which are a preferred model for many cell studies. But understanding this mechanism can be particularly useful in the design of antibiotics because many such drugs specifically target the protein-production process to halt the growth of bacteria.

“We’re trying to understand the process which in the past has proven to be very fruitful as a target for antibiotics,” Ibba said. “The hope is when you target protein synthesis in general, either you stop it completely or make the process too inaccurate so the cell can’t grow.”

This very same quality-control process, involving a different enzyme, is being targeted in the development of an antifungal agent that is currently being tested in humans to treat toenail fungus, Ibba noted.

Even with this second editing step identified, there is still plenty to learn. For example, these enzymes do not act alone. Their interactions with other enzymes in the cell affect their behavior. And exactly what happens when mutant proteins slip through the quality-control system remains poorly understood, as well.


“Sometimes mistakes do get in, and that’s what we’re still uncertain about. Even in some neurodegenerative disorders, we can see that there are almost certainly errors, but the frequency is impossible to know at present,” Ibba said. “If we know more about the mechanism, then if we find mutations, we’ll have a much better chance of finding what the consequences of those mutations are.”

This research was funded primarily by the National Science Foundation, with additional support from the National Institutes of Health and the American Heart Association.

All of the study’s investigators are affiliated with Ohio State’s Center for RNA Biology. Co-authors on the study are Jiqiang Ling of the Biochemistry Program; Byung Ran So in chemistry; Srujana Yadavalli, Herve Roy and Shinichiro Shoji in microbiology; Kurt Fredrick of the Biochemistry Program and microbiology; and Karin Musier-Forsyth of the Biochemistry Program and the departments of chemistry and biochemistry.

More quality control mechanisms:
Discovery Of Protection Against Cell Division Failures
ScienceDaily (Mar. 10, 2009) — ETH researchers have described the causes for division errors of human tissue cells and how the cells protect themselves against these.
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Aurora B delays cell division until chromosome bridges resolve

The researchers identified the already known enzyme Aurora B as an important player in the process. “We noticed that Aurora B stayed active for longer in cells with chromosome bridges”, Gerlich reveals. When Aurora B was active, the daughter cells did not fully separate. The cellular canal containing the chromosome bridge remained open at first, giving the chromosomes enough time to separate. As soon as this was completed, Aurora B was inactivated. This was then the signal for the two daughter cells to fully separate.

When the researchers artificially switched off Aurora B in the experiment, cell division failed as the chromosome bridges formed a barrier. As a result, the cleavage furrow regressed. The daughter cells were not separated and the cell nuclei remained together in the original cell, thus making it tetraploid.

“The experiments suggest that Aurora B responds to non-separated chromosomes and is part of a protective mechanism that ensures that the final step of cell division is only initiated when all chromosomes have been fully separated”, Gerlich explains. Aurora B therefore helps most cells to divide perfectly, even if they have initial difficulties.
 
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Reverse engineering computers that make computers.

Synthetic Biology: Transforming Cells Into Microscopic Biological Computers
ScienceDaily (Mar. 17, 2009) — The roots of synthetic biology stretch back only eight years, and the discipline is so new that it does not yet have an established definition. On the one hand, it can be considered from a microscopic and fundamental perspective – to a certain extent more closely related to chemistry – as the synthesis of new, biologically important molecules (for example, nucleotides). Alternatively, it can be considered at the organism level, understood as the creation of new life forms (such as viruses).

The area between these two areas of research is occupied by a sub-discipline that is “more promising, in that it can help us to understand living systems, focusing on the creation of new genetic circuits – formats for genes and proteins that are connected by complex interactions – that can be integrated into cells to alter their function from that which they would perform in their original context, and the standardization of these circuits so that they can then be combined,” explains Jordi García Ojalvo, a researcher for the Department of Physics and Nuclear Engineering working at the UPC's campus in Terrassa.

One of the current aims of biology researchers is to determine the operation of the genetic circuits that regulate cell activity, a problem that can be solved by adopting an approach derived from engineering. As García Ojalvo explains, “If you want to understand how something works, that is, how a cell carries out a specific task, construct a circuit that does the same thing.” In his view, 'hard science,' which primarily involves the study of inert matter, can also play an important role in the study of living matter.

A researcher with a background in hard science, who understands how these mechanisms function in other types of systems, has the skills required to select a circuit, create a mathematical model using computer simulation and analyze its function. This would make it possible to determine the conditions a circuit requires to perform a specific task. Moreover, a number of techniques and devices used in synthetic biology require the expertise of physicists and engineers, for example, ensuring that cells are handled in a carefully regulated environment (microfluidic control), and providing a high degree of optical precision. The knowledge and data that traditional biologists can provide is also important. As such, synthetic biology is widely considered to be inherently cross-disciplinary.

Although it is a new branch of scientific study, scientists working in synthetic biology did not have to start from scratch, and have been able to draw on decades of work carried out in fields such as genetic engineering, molecular biology and, more recently, systems biology. Specific milestones that have contributed to the development of synthetic biology include the discovery of the green fluorescent protein and its use as a marker in the analysis of various processes in all areas of biology, which is now a standard technique that enables scientists to observe the responses of individual cells to different actions and monitor their status in real time.

An enhanced version of nature

One of the most novel aspects of this discipline is its inherent capacity for a key concept: standardization. To draw a comparison with electronics, in the same way that a hard disk can be connected to any computer, so genetic circuits can be integrated into any cell to prompt a specific task.

Given the difficulties of analyzing the complex genetic circuits found in nature, synthetic biology offers an alternative approach to the problem: construct the simplest circuits possible, determine how they function, and increase the level of complexity step by step. Since research of this type focuses on simple circuits, involving only two or three genes, it is possible to develop mathematical models that are not only capable of predicting cell behavior in terms of the degree of protein production but can also induce specific dynamics.

This was first achieved in 2000 by a research group directed by Michael Elowitz, at the California Institute of Technology (Caltech), which constructed the first oscillator, or synthetic genetic clock. This breakthrough, which effectively marked the inception of synthetic biology as a discipline, demonstrated that cells have a built-in 'clock' which enables them to calculate time and synchronize to perform predetermined actions simultaneously.

Since then, research in this field in Spain has been carried out jointly with groups such as the UPC's Research Group on Nonlinear Dynamics, Nonlinear Optics and Lasers (DONLL), based at the Terrassa campus, coordinated by Ramon Vilaseca and formed by researchers including García Ojalvo. The group has spent six years working in the fields of synthetic biology and systems biology, first concentrating on theory and then moving into experimental work in the last two years. Research conducted in collaboration with the Elowitz group at Caltech and a group coordinated by Gurol Suel of the University of Texas Southwestern Medical Center at Dallas focuses on understanding differentiation processes (such as state changes) in bacteria, which are model organisms that can be used to study functions performed in more complex organisms.

The DONLL team is also working with a research group coordinated by Alfonso Martínez Arias, of the University of Cambridge, to understand the process by which embryonic stem cells maintain multipotentiality, which is the mechanism through which they conserve the capacity to differentiate into any type of cell. In this specific area, researchers do not use synthetic biology per se – they do not construct circuits, for example – but try to analyze the way in which natural circuits function. Although the work of the DONLL group is not yet targeted at a specific application, the general objective is to develop the capability to control cell behaviour externally.

Understanding living systems


One of the most notable aspects of synthetic biology, in the view of many researchers, is that it can help us to better understand living organisms. It could therefore become a fundamental tool for understanding cell machinery, as it illustrates the range of tasks that can be carried out by the components responsible for biological functions. Scientists working in this discipline are able to take a more quantitative approach to biology in general, by using models to make predictions that can then be tested in laboratory conditions.

The challenge facing researchers in synthetic biology is considerable, particularly if we consider that the human genome contains thirty thousand genes and a cell contains around one million proteins. However, a cell is more than just the sum of its parts, and its functions should be interpreted taking into account the complex combination of components involved, since the genes and proteins that make up the genome are interlinked by millions of individual connections.

For now, the aim of this discipline is simply to satisfy our curiosity, to gradually increase scientific understanding of the potential of interactions between genes and proteins, and to define and characterize the flow of information that triggers a biological process.

Bioremediation

When asked about their expectations regarding the development of synthetic biology (one of its principal applications is likely to be biomedicine), experts suggest that it will not produce many short-term applications. Nevertheless, there are already notable examples in the field of drug synthesis: a team from the Lawrence Berkeley National Laboratory in California has reconstructed in the bacteria E. coli the genetic circuit responsible for synthesizing the precursor to the anti-malarial drug artemisinin, which should lead to cheaper and more efficient production.

The environment may be the next field to benefit from advances in synthetic biology. For example, work is currently underway to design more efficient microorganisms for decontaminating ecosystems (bioremediation). Researchers are also developing biosensor devices, which will be able to recognize target substances and microorganisms and interact with them.

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