Here’s a comment on work published about 6 months ago that was relevant to me, given my graduate studies on FAK with Jun-Lin Guan. The relations between protein structures and evolution are quite interesting indeed.

As more structures are being solved for multimodular signaling proteins, the regulatory kinetics (on, off, and everything in between) is coming into greater clarity. For instance, the recently solved structural basis for allosteric autoinhibition of focal adhesion kinase (FAK), along with the ZAP-70 tyrosine kinase, and the protypical tyrosine kinase Src.

As with all comparisons within protein families involving crystallography, the stories that come out of the research relate to the structural plasticity of the crystals themselves, and how homologous proteins (of both orthologous and paralogous flavors) find such diverse regulatory mechanisms. For kinases in general, we have the basic catalytic unit, which evolved long before the advent of eukaryotic cells, and diverged into tyrosine, serine/threonine, lipid, and atypical phosphorylating enzymes by many gene duplication and exaption events.

For individual kinase subfamilies, innovative mechanisms¹ for modulating catalytic activity abound. Every part of a protein not absolutely required (or conserved) for catalytic activity becomes a candidate enhancing mutation, enabling both complexity and control. Read more »

Two blog posts recently collided for me. First, in a blog discussion on Macroevolution vs. Microevolution, Allen MacNeill clarified some issues for me (thanks to TUIBG for bringing it back up):

Add the newly emerging fields of evo-devo and epigenesis to the foregoing, and it is increasingly clear that macroevolution (i.e. cladogenesis) follows different rules than microevolution (i.e. anagenesis), and that these differences are most noticeable in the fossil record cited by Eldredge and Gould as the basis for their theory of punctuated equilibrium. In particular, the basic program that energized the “modern synthesis” – that is, the reduction of all significant evolutionary mechanisms to a series of linked mathematical models, based on grossly simplified reductions of complex biology to quasi-Mendelian point-like “particles of inheritance” (changes in which drive the variation and divergence of phenotypes) – is impossible to apply in any coherent way to macroevolution. The “modern synthesis” was essentially a “Newtonian” program, whose proponents assumed that the underlying law-like processes (i.e. microevoluiton) are (like physics) both ahistorical and universal. However, it is now becoming clear that the emerging science of macroevolution is both irreversibly historically contingent (and therefore not reducible to mathematical formalisms) and driven by fundamentally different processes than those underlying most of microevolution.

Rich Lawler’s comment at Gene Expression counter-balances that comment with an item on Formalization and Process:

It’s interesting to note that a few of the most insightful observations about the evolutionary process were first promulgated verbally, then later proven mathematically (unlike H-W equilibrium). These include runaway sexual selection (first adumbrated by Fisher, then shown mathematically possible by Lande and Kirkpatrick), the handicap principle (first adumbrated by Zahavi, then–finally–shown to be mathematically possible by Grafen), and, of course, natural selection (first adumbrated by what’s-his-face, then formalized by Wright, Fisher, and later Price, among others). And of course, all of these topics were debated back-n-forth until the math made them more clear.

Read more »

Amid the political controversy and obstructions to conducting stem cell research, scientists this year managed to turn lead into gold… Genetically manipulating fibroblasts to become ESC(embryonic stem cell)-like sort of sounds like alchemy in a way, doesn’t it? The product of these papers, inducible pluripotent stem (iPS) cells, were created by transfecting four factors into fibroblasts, Oct3/4, Sox2, c-Myc, and Klf4, and they found that the epigenetic, morphological, and proliferative characteristics resembled those of embryonic stem cells. Read more »

As always, it’s these odd conjunctions of things that don’t go together that catches the eye. In this case, molecular and sociology. The actual article¹ is much more mundane and true to the correct science jargon, and included in a special section of the most recent Nature on “Proteins to Proteomes.” It’s also a nice article that examines a broad array of topics in molecular biology.

Of greater interest and with a slightly less catchy title, is another article on the section: Reaching for high-hanging fruit in drug discovery at protein–protein interfaces². The abstract: Read more »

A recent article in Science discussed a claim made by Bill and Melinda Gates, where they proposed that malaria could be eradicated from the Earth over the next few decades. Vanquishing disease is seen as the ultimate goal in medical science, and many dream of the day that we will all be living longer and healthier lives. But the real question is, how do you beat something that will always outrun you? Read more »

Cognition is a term frequently used in several loosely related ways to refer to a faculty for the human-like processing of information. Signal transduction networks certainly fit that bill, as the mediate adaptive changes in gene expression to specific sensory inputs. Melinda Baker and Jeffry Stock, in the recent issue of Current Biology, elaborate on modalities of such cognition in bacteria: Networks and integrated circuits in bacterial cognition.

Of course, they’re not quite circuits in the electrical engineering sense either. Think chemical networking, where each biomolecule in a signaling network can interact with a variety of other molecules, with varying interaction kinetics, and where each interaction has the potential to impact additional outcomes. Coupled with the selection of functions in the micro-environmental milieu, cellular networks ended up organized in efficient ways to control motility, metabolism, growth, and eventually higher processes.

But just suppose for a moment that a cell, even a bacterium, didn’t merely process inputs from the micro-environment. Some people suggest that the information processing, regulatory feedback loops, and adaptive response to stimuli, constitute something else: Read more »

Myosin II functions as a molecular motor which facilitates contraction of the actin cytoskeleton during migration, resides outside of protrusions at the front of motile cells, and acts at a distance to impact cell protrusion, signaling, and maturation of nascent adhesions. So clearly myosin II is a protein that is of great importance for understanding cell migration.

But Myosin II is not just one protein. There are actually two isoforms of this protein that are not identical, just very very similar. I’m not familiar with where in the natural history of cells the genes for these two proteins diverged, but they’re clearly derived from a single ancestral gene. And beyond that, there are quite a few other myosins which are more distantly similar (the list easily goes into double-digits)¹.

Vicente-Manzanares et al.², in their paper, determine the divergent functions of myosin IIA (MIIA) and MIIB, and find that these isoforms have become suited to spatial and functional niches within the cell. They found: Read more »

On a couple other blogs, a study published in Science by Joan Steitz¹ is being called “One of the biggest findings of the year,” and “If it turns out to be true, this finding just flipped the whole field on its head.” Bitesize Bio would be greatly remiss to not mention to so hot a story, joining in with The Daily Transcript and One Random Scientist.

The abstract, from Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation: Read more »

There might be more to cell death besides apoptosis and necrosis. In a paper that sounded a bit fishy to me, Michael Overholtzer, Joan Brugge and coworkers¹ introduce “Entosis”: A non-apoptotic cell death process, that occurs by cell-in-cell invasion.

As Eileen White² described:

Upon examination of mammary epithelial cell lines in suspension, Overholtzer et al. noticed the presence of cells within other cells. Further investigation of this phenomenon revealed that detachment of mammary epithelial cells from the ECM initiates a new pathway of nonapoptotic cell death called entosis in which one cell invades into another.

Read more »

Looking at the tree of life, descent with modification is an obvious theme, where genes are passed on through ‘vertical’ lines of ancestry. It so happens though that genes can jump from one lineage to another, by a process called ‘horizontal gene transfer’ (HGT). Naked DNA uptake (transformation), viruses (transduction), and plasmids (conjugation) are the mechanisms by which the genetic units of heredity need not be inherited in the usual sense. HGT appears to blur the boundaries of what a species is, particularly for the bacterial domain of life. So the study published by Rotem Sorek, Edward Rubin et al.¹ on the determination of barriers to HGT is interesting from a couple different perspectives. Read more »