Structural principles that enable oligomeric small heat-shock protein paralogs to evolve distinct functions

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Science  23 Feb 2018:
Vol. 359, Issue 6378, pp. 930-935
DOI: 10.1126/science.aam7229

Putting distance between protein relatives

Many proteins form complexes to function. When the gene for a self-assembling protein duplicates, it might be expected that the related proteins (paralogs) would retain interfaces that would allow coassembly. Hochberg et al. show that the majority of paralogs that oligomerize in fact self-assemble. These paralogs have more diverse functions than those that coassemble, implying that maintaining coassembly would constrain evolution of new function. The authors experimentally investigated how two oligomeric small heat-shock protein paralogs avoid coassembly and found that flexibility at regions outside of the interaction interfaces played a key role.

Science, this issue p. 930


Oligomeric proteins assemble with exceptional selectivity, even in the presence of closely related proteins, to perform their cellular roles. We show that most proteins related by gene duplication of an oligomeric ancestor have evolved to avoid hetero-oligomerization and that this correlates with their acquisition of distinct functions. We report how coassembly is avoided by two oligomeric small heat-shock protein paralogs. A hierarchy of assembly, involving intermediates that are populated only fleetingly at equilibrium, ensures selective oligomerization. Conformational flexibility at noninterfacial regions in the monomers prevents coassembly, allowing interfaces to remain largely conserved. Homomeric oligomers must overcome the entropic benefit of coassembly and, accordingly, homomeric paralogs comprise fewer subunits than homomers that have no paralogs.

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