A hydrophobic ratchet entrenches molecular complexes

Abstract

Most proteins assemble into multisubunit complexes 1 . The persistence of these complexes across evolutionary time is usually explained as the result of natural selection for functional properties that depend upon multimerization, like intersubunit allostery or the capacity to do mechanical work 2 . In many complexes, however, multimerization does not enable any known function 3 . An alternative explanation is that multimers could become entrenched if substitutions accumulate that are neutral in multimers but deleterious in monomers; purifying selection would then prevent reversion to the unassembled form, even if assembly per se does not enhance biological function 3 – 7 . Here we show that a hydrophobic mutational ratchet systematically entrenches molecular complexes. By applying ancestral protein reconstruction and biochemical assays to the evolution of steroid hormone receptors (SRs), we show that an ancient hydrophobic interface, conserved for hundreds of millions of years, is entrenched because exposing this interface to solvent reduces protein stability and causes aggregation, despite making no detectable contribution to function. Using structural bioinformatics, we show that a universal mutational propensity drives sites that are buried in multimeric interfaces to accumulate hydrophobic substitutions to levels not tolerated in monomers. In a database of hundreds of families of multimers, the majority show signatures of long-term hydrophobic entrenchment. It is therefore likely that many protein complexes persist because a simple ratchet-like mechanism entrenches them across evolutionary time, even when they are functionally gratuitous.

Haven't got a glue: Protein surface variation for the design of molecular glue degraders

“…The mechanism of action of GNE-0011 has not been reported to date. patches have been suggested to persist as means to favor functionally relevant multimerization (Hochberg et al, 2020). Surface-bound small molecules could thus similarly conjure a sufficiently hydrophobic hotspot to either lead to target aggregation or induce higher-order assemblies.…”

Large protein complex interfaces have evolved to promote cotranslational assembly

“…In other words, can it increase cellular fitness enough to influence the course of proteome evolution? Cotranslational assembly may well represent a ratchet-like mechanism of constructive neutral evolution 55,58 , whereby a drift in interface properties creates ideal conditions for assembly on the ribosome. Reversion to the post-translational route is prevented by the accumulation of mutations that are neutral in the cotranslationally entrenched subunit, but would otherwise be deleterious in the ancestor.…”

“…According to this, the largest interfaces in a complex correspond to the earliest forming subcomplexes within the assembly pathway, irrespective of how binding is initiated. While the presence of specific contacts that increase affinity could introduce compositional biases into the sequence space exerting undue selection pressure on proteomes, variability in interface size can emerge from non-adaptive processes as the organising principle of cotranslational assembly [53][54][55][56][57][58] . In the present study, we address this idea by analysing assembly-onset positions determined by ribosome profiling of human complexes 16 and by comparing areas of first and last translated interfaces in multi-interface heteromers.…”

The structure of evolutionary theory: Beyond Neo-Darwinism, Neo-Lamarckism and biased historical narratives about the Modern Synthesis

“…There is some recent experimental evidence for CNE from a study of long-term evolution of vertebrate steroid receptors that have increased in complexity simply through neutral evolution (Hochberg et al 2020). Such neutral evolution acted in a ratchet-like fashion, leading to a state where current complexity is maintained by purifying selection (Hochberg et al 2020).…”

“…There is some recent experimental evidence for CNE from a study of long-term evolution of vertebrate steroid receptors that have increased in complexity simply through neutral evolution (Hochberg et al 2020). Such neutral evolution acted in a ratchet-like fashion, leading to a state where current complexity is maintained by purifying selection (Hochberg et al 2020). I strongly suspect that Müller and other EES-proponents with their strong focus on organismal phenomena are not very interested in such neutral evolution at the molecular level and its consequences.…”