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How structural and physicochemical determinants shape sequence constraints in a functional enzyme.

ABSTRACT: The need for interfacing structural biology and biophysics to molecular evolution is being increasingly recognized. One part of the big problem is to understand how physics and chemistry shape the sequence space available to functional proteins, while satisfying the needs of biology. Here we present a quantitative, structure-based analysis of a high-resolution map describing the tolerance to all substitutions in all positions of a functional enzyme, namely a TEM lactamase previously studied through deep sequencing of mutants growing in competition experiments with selection against ampicillin. Substitutions are rarely observed within 7 Å of the active site, a stringency that is relaxed slowly and extends up to 15-20 Å, with buried residues being especially sensitive. Substitution patterns in over one third of the residues can be quantitatively modeled by monotonic dependencies on amino acid descriptors and predictions of changes in folding stability. Amino acid volume and steric hindrance shape constraints on the protein core; hydrophobicity and solubility shape constraints on hydrophobic clusters underneath the surface, and on salt bridges and polar networks at the protein surface together with charge and hydrogen bonding capacity. Amino acid solubility, flexibility and conformational descriptors also provide additional constraints at many locations. These findings provide fundamental insights into the chemistry underlying protein evolution and design, by quantitating links between sequence and different protein traits, illuminating subtle and unexpected sequence-trait relationships and pinpointing what traits are sacrificed upon gain-of-function mutation.

SUBMITTER: Abriata LA

PROVIDER: S-EPMC4338278 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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How structural and physicochemical determinants shape sequence constraints in a functional enzyme.

Abriata Luciano A LA Palzkill Timothy T Dal Peraro Matteo M

PloS one 20150223 2

The need for interfacing structural biology and biophysics to molecular evolution is being increasingly recognized. One part of the big problem is to understand how physics and chemistry shape the sequence space available to functional proteins, while satisfying the needs of biology. Here we present a quantitative, structure-based analysis of a high-resolution map describing the tolerance to all substitutions in all positions of a functional enzyme, namely a TEM lactamase previously studied thro ...[more]

PMID: 25706742

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Project description:BackgroundProteins show a broad range of evolutionary rates. Understanding the factors that are responsible for the characteristic rate of evolution of a given protein arguably is one of the major goals of evolutionary biology. A long-standing general assumption used to be that the evolution rate is, primarily, determined by the specific functional constraints that affect the given protein. These constrains were traditionally thought to depend both on the specific features of the protein's structure and its biological role. The advent of systems biology brought about new types of data, such as expression level and protein-protein interactions, and unexpectedly, a variety of correlations between protein evolution rate and these variables have been observed. The strongest connections by far were repeatedly seen between protein sequence evolution rate and the expression level of the respective gene. It has been hypothesized that this link is due to the selection for the robustness of the protein structure to mistranslation-induced misfolding that is particularly important for highly expressed proteins and is the dominant determinant of the sequence evolution rate.ResultsThis work is an attempt to assess the relative contributions of protein domain structure and function, on the one hand, and expression level on the other hand, to the rate of sequence evolution. To this end, we performed a genome-wide analysis of the effect of the fusion of a pair of domains in multidomain proteins on the difference in the domain-specific evolutionary rates. The mistranslation-induced misfolding hypothesis would predict that, within multidomain proteins, fused domains, on average, should evolve at substantially closer rates than the same domains in different proteins because, within a mutlidomain protein, all domains are translated at the same rate. We performed a comprehensive comparison of the evolutionary rates of mammalian and plant protein domains that are either joined in multidomain proteins or contained in distinct proteins. Substantial homogenization of evolutionary rates in multidomain proteins was, indeed, observed in both animals and plants, although highly significant differences between domain-specific rates remained. The contributions of the translation rate, as determined by the effect of the fusion of a pair of domains within a multidomain protein, and intrinsic, domain-specific structural-functional constraints appear to be comparable in magnitude.ConclusionFusion of domains in a multidomain protein results in substantial homogenization of the domain-specific evolutionary rates but significant differences between domain-specific evolution rates remain. Thus, the rate of translation and intrinsic structural-functional constraints both exert sizable and comparable effects on sequence evolution.

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How structural and physicochemical determinants shape sequence constraints in a functional enzyme.

Publications

How structural and physicochemical determinants shape sequence constraints in a functional enzyme.

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