Saturday, July 12, 2014

Chaperones Step in to Increase Evolution's Promiscuity

Mutations are usually bad, but can be made less bad with some protein folding help.

Proteins are the central mechanics of life, catalyzing the reactions, lifting the loads, purifying the fluids, and expressing the genes. They are also the most frequent targets of damaging mutations in their encoding genes. Some of these mutations happen outside the amino acid coding regions, in regulatory areas, but the most dramatic ones are typically within the coding region, changing the amino acid sequence.

Such mutations can not only change the function of a protein, but can also change its stability- its ability to fold and stay folded. Random polypeptides typically do not fold in any coherent way, in contrast to biologically evolved proteins, so the ability to fold tightly is weakened by most mutations.

Here is where saviors come into the picture- the chaperones, which are proteins specialized to help other proteins fold. The most massive of these feature a large cave whose internal surface can switch, with consumption of ATP, between hydrophobic and hydrophilic surfaces. It is like sticking your protein inside a jiffy-pop dome that can alternately encourage unfolding and folding in a protected, isolated space, until the protein gets it all together. Remember that the insides of proteins tend to be hydrophobic, and the outsides tend to be hydrophilic, which helps to direct the folding path in normal proteins, in addition to detailed spatial and electrostatic relationships among the amino acids.

Structural aspects of one chaperone, GroES/GroEL, within which other proteins (purple & yellow, in d) other proteins can fold in isolation. As shown in C, the interior can switch, using ATP, between hydrophobic and hydrophilic surfaces, encouraging folding and unfolding, respectively. Thus even without knowing how the protein is supposed to fold, this chaperone can, given enough time and energy, bias the folding pathway towards folding. It also seems to be able to detect that it contains a folded protein, prompting opening of the chamber.

Like stability, solubility is another danger. Proteins that are not sufficiently hydrophilic on their outsides tend to glomb together and create scrambled clots in cells, like we find in brains with dementia. Keeping proteins from aggregating is another job for chaperone proteins, which can pull such proteins apart, and / or tag them for degradation altogether.

A recent paper describes how chaperones can help to buffer organisms from the effects of modestly deleterious mutations, allowing a more diverse landscape of mutations in a population than otherwise possible. This is not a new idea, but the researchers try to put a more quantitative spin on it, and look in novel places for the effects chaperones have.
"For instance, enhancing chaperone capacity through over-expression has been directly shown to promote enzyme evolvability. Chaperones have been found to act both as genotypic and phenotypic capacitors."

Some of the most interesting bits of work concern protein interaction networks. Over the years, biologists have found that the cell full of proteins is a little like the internet, with lots of interactions between various proteins. There are some very dense sub-networks with a few hub proteins that have many partners, and then more peripheral proteins. These hub proteins tend to have a bit more disorder in their protein structure, perhaps because their many interactions require a bit of hydrophobic exposed area for each one (or else a floppy region that hides the interaction area prior to the partner's appearance). So these proteins are particularly dependent on chaperone assistance in folding:
"Upon deletion of [chaperone] SSB, 50% of the hub proteins, but less than 10% of the non-hubs aggregate immediately."
Hub proteins, by the author's analysis, tend to be more frequent "clients" of chaperones such as Hsp90 and Hsp70, and have more disordered regions in their structure.

They also do an interesting survey of the degree of rewiring of such protein networks between the distantly related yeast species, S. cerevisiae and S. pombe, to set up a metric of which proteins have maintained pretty much the same function, vs those whose partnerships have changed the most (i.e. become "rewired"). They then use two metrics of evolutionary change within protein sequences, the non-synonymous vs synonymous mutation rate, and second they devise a new conservative vs non-conservative change metric for mutations that are non-synonymous. This allows them to find that while highly rewired proteins tend to have lower than average non-synonymous mutation rates, befitting their key status in their networks, (i.e. increased purifying selection), they also have higher than average non-conservative amino acid mutations, perhaps as a sign of positive selection at key spots, plus, of course, the assistance that chaperones provide to enable structurally marginal mutants to survive.
"[Chaperone] Hsp90 was found to promote protein evolutionary rates in strong substrates [dependent on Hsp90 assistance for folding] when assessed by dN or ω [metrics of degree of change in protein sequences]."

Such analyses can help us dive ever deeper into the details of evolutionary history, given the vast resources of the genome sequences now available at every turn. In this case, it emphasizes that while each protein, indeed each nucleotide position, is an individual case, we can make some crude generalizations from sequence to function and back again. For the chaperones, it is evident that they are most important for difficult proteins, whether by intrinsic design in the interaction vs independent folding tradeoff, or temporarily after a damaging mutation, which may be resolved back to the original state eventually, or to some new state with new significance for the organism.

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