David Fernandez Bonet, Shahrayar Ranyai, Luay Aswad, David P. Lane, Marie Arsenian-Henriksson, Michael Landreh, Dilraj Lama
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引用次数: 0
Abstract
Homorepeats are motifs with reiterations of the same amino acid. They are prevalent in proteins associated with diverse physiological functions but also linked to several pathologies. Structural characterization of homorepeats has remained largely elusive, primarily because they generally occur in the disordered regions or proteins. Here, we address this subject by combining structures derived from machine learning with conformational sampling through physics-based simulations. We find that hydrophobic homorepeats have a tendency to fold into structured secondary conformations, while hydrophilic ones predominantly exist in unstructured states. Our data show that the flexibility rendered by disorder is a critical component besides the chemical feature that drives homorepeats composition toward hydrophilicity. The formation of regular secondary structures also influences their solubility, as pathologically relevant homorepeats display a direct correlation between repeat expansion, induction of helicity, and self-assembly. Our study provides critical insights into the conformational landscape of protein homorepeats and their structure-activity relationship.
期刊介绍:
Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome.
In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.