Tag Archives: protein

Mapping the Human Proteome

The human genome is old news. Next stop: the human proteome

Unlike the genome, which remains essentially static between cell types and over time, the proteome is tremendously dynamic, changing constantly in response to cell-cell signalling and environmental stimuli. Thus even though -with some small exceptions – every cell in your body carries the same genome, the proteome can be wildly different between different tissues and can change rapidly over time
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At the very least, large-scale analysis of the human proteome should allow researchers to tentatively place many of our currently anonymous genes into functional pathways. That’s a step forward for personal genomics: knowing that you have a loss-of-function mutation in a gene that may be involved in cholesterol biosynthesis is a lot more useful (in terms of guiding further clinical testing) than simply knowing that you have a mutation in hypothetical gene C11orf68.

The Subtly Different Squid Eye

The subtly different squid eye by PZ Myers:

the inside out organization of the cephalopod eye relative to ours: they have photoreceptors that face towards the light, while we have photoreceptors that are facing away from the light. There are other important differences, though, some of which came out in a recent Nature podcast with Adam Rutherford, which was prompted by a recent publication on the structure of squid rhodopsin.

Superficially, squid eyes resemble ours. Both are simple camera eyes with a lens that projects an image onto a retina, but the major details of these eyes evolved independently – the last common ancestor probably had little more than a patch of light sensitive cells with an opsin-based photopigment. The general properties of this ancient eye can still be seen in modern eyes. They detect light with a simple molecule called retinal that is capable of absorbing a photon, changing its shape from the 11-cis form to the all trans form; basically, it flips from a chain with a kink to a straight chain. Retinal is imbedded in a protein called opsin. When retinal changes shape, it changes the shape of the opsin protein, too, which can then interact with other proteins in the cell membrane.

The next protein in the sequence is called a G protein. G proteins are ubiquitous intermediates for many cellular processes; when a receptor, like opsin, is activated, it activates a G protein, which then activates other proteins, starting a signaling cascade. In the podcast, I compare this to starting an avalanche. Opsin is an agent standing on a hill; when it receives a light signal, it nudges a small boulder (the G protein), which then tumbles down setting a whole series of rocks in motion. The G protein is an intermediate which takes a small change, the initial nudge, and amplifies it into the activation of many other proteins.

Vaccine For Strep Infections

Engineered Protein Shows Potential as a Strep Vaccine

A University of California, San Diego-led research team has demonstrated that immunization with a stabilized version of a protein found on Streptococcus bacteria can provide protection against Strep infections, which afflict more than 600 million people each year and kill 400,000.
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Group A Streptococcus (GAS). GAS causes a wide variety of human diseases including strep throat, rheumatic fever, and the life-threatening “flesh-eating” syndrome called necrotizing fasciitis. Studies were performed using M1 protein, which represents the version of M protein present on the most common disease-associated GAS strains.
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“We created a modified version of M1 with a more stable structure, and found that it is just as effective at eliciting an immune reaction, but safer than the original version of M1, which has serious drawbacks to its use in a vaccine.”

New Approach Builds Better Proteins Inside a Computer

With the aid of more than 150,000 home computer users throughout the world, Howard Hughes Medical Institute (HHMI) researchers have, for the first time, accurately predicted the three-dimensional structure of a small, naturally occurring globular protein using only its amino acid sequence. The accomplishment was achieved with a newly refined computational method for predicting protein structure, which the researchers say can also improve the detail and accuracy of protein structures generated with experimental techniques.

A detailed understanding of a protein’s structure can offer scientists a wealth of information – revealing intricacies about the protein’s biological function and suggesting new ideas for drug design. Researchers often rely on x-ray crystallography to determine a protein’s structure – bombarding the molecule with x-rays and analyzing the resulting diffraction pattern to piece together its structure. But not all proteins are amenable to this time-consuming technique, and those that are do not always yield the atomic-level data researchers would like to have.
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The complex algorithms the researchers developed to carry out these analyses demand a tremendous amount of computing power. More than 150,000 home computer users around the world were an integral part of the project, volunteering their computers to participate in the quest for protein structures through Rosetta@home, a distributed computing project that is based on the Berkeley Open Infrastructure for Network Computing (BOINC) platform.

You can join in via Rosetta@home. Related: Protein Knots – molecular sieve advances protein research – Protein Science Art – Nobel Laureate Discusses Protein Power

Clues to Prion Infectivity

Structural Studies Reveal New Clues to Prion Infectivity

One of the unexplained questions facing prion researchers is how a single prion can apparently assume different conformations — with each conformation having different disease or phenotypic properties. Previous structural studies of prions had not yielded a clear understanding of the basis of strains because the prion protein is large and complex. Due to the size and complexity of prions, studies utilizing x-ray crystallography, a technique commonly used to determine the structure of proteins and other molecules, have been limited to short peptide fragments of the prion protein.

“There have been a number of fairly low-resolution pictures of prions that more or less proved that these different strains were in different conformations; but they really hadn’t established the nature of the different conformations,” Weissman said. “It was really a big black box. We basically didn’t have the conformation of any single prion, let alone the two prion protein strains in two different conformations.”
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““In our minds, our findings brought to a certain level of closure the understanding of the structural differences underlying strains,” said Weissman. “Now we understand the structural differences. We also have an idea how those differences lead to the differences in physical properties, and, in turn, how these differences in the physical properties lead to the phenotypic differences. We are starting to go all the way from the structural understanding of the different strains up to in vivo understanding of why they cause different behaviors inside the cell.”

Weissman noted that the findings offer a broader lesson to researchers studying prions and other proteins whose misfolding can cause disease. “Certainly, a bottom line from this study is that the rules of protein folding and the rules of protein misfolding are fundamentally different,” he said. “In many ways, we have to relearn basic principles of how proteins misfold. We have to forget many of the rules we learned from textbooks about protein folding because they are not necessarily applicable.”

Prions are very interesting. Related posts: Scientists Knock-out Prion Gene in Cows – Gene Study Finds Cannibal Pattern – Open Access Education Materials on Protein Folding

ScienceMatters@Berkeley April 2007

As usually the latest issue of ScienceMatters@Berkeley includes several intersting articles including, The Protein Machine by Kathleen M. Wong

A large percentage of known antibiotics target bacterial ribosomes, including tetracycline, erythromycin, and streptomycin. Many of these antibiotics have been isolated from microbes themselves. “It’s a byproduct of the chemical warfare that’s been going on among bacteria for hundreds of millions of years,” Cate says. “We want to understand how these natural products inhibit translation. Then, based on what we understand about the ribosome mechanism, we should be able to come up with new ways to stop bacterial translation based on the old compounds.”

Self-Tuning Genes:

Researchers such as UC Berkeley’s Adam Arkin have found that regulatory feedback is associated with chance fluctuations in mRNA or protein levels—a phenomenon called expression noise. “Even though they’re all genetically identical, and grown under the same conditions, yeast clones don’t express certain proteins at exactly the same level,” Brem says. “Some genes are noisier than others. That makes people think the cell is actively tuning the distribution around an expression level set by the regulatory network.” Noise may ensure that a few individuals can handle abrupt changes in their environment. In other words, if a colony is suddenly assaulted by toxic chemicals or high heat, a few individuals will already have expression levels suited to those conditions.

Protein Knots

graphic of human ubiquitin hydrolase

Knotty problem puzzles protein researchers by Anne Trafton:

Knots are rare in proteins–less than 1 percent of all proteins have any knots, and most are fairly simple. The researchers analyzed 32,853 proteins, using a computational technique never before applied to proteins at this scale.

Of those that had knots, all were enzymes. Most had a simple three-crossing, or trefoil knot, a few had four crossings, and the most complicated, a five-crossing knot, was initially found in only one protein–ubiquitin hydrolase.

That complex knot may hold some protective value for ubiquitin hydrolase, whose function is to rescue other proteins from being destroyed–a dangerous job.

Photo: MIT researchers recently found that human ubiquitin hydrolase, shown here, has the most complicated knot ever observed in a protein. The simplified diagram, inset, shows the knot in the protein, which crosses itself five times. Larger image.

MIT’s molecular sieve advances protein research

Separating proteins from complex biological fluids such as blood is becoming increasingly important for understanding diseases and developing new treatments. The molecular sieve developed by MIT engineers is more precise than conventional methods and has the potential to be much faster.
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The key to the molecular sieve, which is made using microfabrication technology, is the uniform size of the nanopores through which proteins are separated from biological fluids. Millions of pores can be spread across a microchip the size of a thumbnail.
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Juhwan Yoo, a Caltech undergraduate, also participated in the research as a summer visiting student. Funding came from the National Science Foundation, the National Institutes of Health and the Singapore-MIT Alliance.