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A hydrophobic ratchet entrenches molecular complexes

Hochberg, Georg K A ; Liu, Yang ; Marklund, Erik G ; Metzger, Brian P H ; Laganowsky, Arthur ; Thornton, Joseph W

Nature (London), 2020-12, Vol.588 (7838), p.503-508 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
A hydrophobic ratchet entrenches molecular complexes
Autor: Hochberg, Georg K A ; Liu, Yang ; Marklund, Erik G ; Metzger, Brian P H ; Laganowsky, Arthur ; Thornton, Joseph W
Assuntos: Binding Sites - genetics ; Biochemistry ; Bioinformatics ; Biokemi ; Biologi med inriktning mot evolutionär funktionsgenomik ; Biology with specialization in Evolutionary Functional Genomics ; Chemical properties ; Deoxyribonucleic acid ; DNA ; DNA - metabolism ; Evolution, Molecular ; Experiments ; Genetic aspects ; Humans ; Hydrophobic and Hydrophilic Interactions ; Hydrophobic effect ; Hydrophobic surfaces ; Hydrophobicity ; Interface stability ; Interfaces ; Ligands ; Models, Molecular ; Monomers ; Multiprotein Complexes - chemistry ; Multiprotein Complexes - genetics ; Multiprotein Complexes - metabolism ; Mutant Proteins - chemistry ; Mutant Proteins - genetics ; Mutant Proteins - metabolism ; Mutation ; Mutation (Biology) ; Natural history ; Natural selection ; Physiological aspects ; Protein Aggregates ; Protein Domains ; Protein Multimerization - genetics ; Protein Stability ; Proteins ; Receptors, Steroid - chemistry ; Receptors, Steroid - genetics ; Receptors, Steroid - metabolism ; Reversion ; Solvents ; Solvents - chemistry ; Steroid hormone receptors ; Steroid hormones ; Steroids
É parte de: Nature (London), 2020-12, Vol.588 (7838), p.503-508
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Author contributions. GKAH and JWT conceived the project and oversaw the manuscript writing. GKA performed phylogenetics, ancestral sequence reconstruction, protein purification, cell culture, and biophysical experiments. YL and AL performed and interpreted native MS experiments. EGM performed and analyzed molecular dynamics simulations. GKAH and BPHM designed bioinformatic analyses, which GKAH performed. GKAH and JWT interpreted all data. All authors contributed to manuscript writing.
Descrição: Most proteins assemble into multisubunit complexes . The persistence of these complexes across evolutionary time is usually explained as the result of natural selection for functional properties that depend on multimerization, such as intersubunit allostery or the capacity to do mechanical work . In many complexes, however, multimerization does not enable any known function . 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 . 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, we show that an ancient hydrophobic interface, conserved for hundreds of millions of years, is entrenched because exposure of this interface to solvent reduces protein stability and causes aggregation, even though the interface makes 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 that are not tolerated in monomers. In a database of hundreds of families of multimers, most 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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A hydrophobic ratchet entrenches molecular complexes

Hochberg, Georg K A ; Liu, Yang ; Marklund, Erik G ; Metzger, Brian P H ; Laganowsky, Arthur ; Thornton, Joseph W

England: Nature Publishing Group

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