Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH
AffiliationDepartment of Cellular & Molecular Medicine, University of Arizona
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PublishereLife Sciences Publications Ltd
CitationHwang, T., Parker, S. S., Hill, S. M., Grant, R. A., Ilunga, M. W., Sivaraman, V., Mouneimne, G., & Keating, A. E. (2022). Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH. ELife.
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AbstractThe human proteome is replete with short linear motifs (SLiMs) of four to six residues that are critical for protein-protein interactions, yet the importance of the sequence surrounding such motifs is underexplored. We devised a proteomic screen to examine the influence of SLiM sequence context on protein-protein interactions. Focusing on the EVH1 domain of human ENAH, an actin regulator that is highly expressed in invasive cancers, we screened 36-residue proteome-derived peptides and discovered new interaction partners of ENAH and diverse mechanisms by which context influences binding. A pocket on the ENAH EVH1 domain that has diverged from other Ena/VASP paralogs recognizes extended SLiMs and favors motif-flanking proline residues. Many high-affinity ENAH binders that contain two proline-rich SLiMs use a noncanonical site on the EVH1 domain for binding and display a thermodynamic signature consistent with the two-motif chain engaging a single domain. We also found that photoreceptor cilium actin regulator (PCARE) uses an extended 23-residue region to obtain a higher affinity than any known ENAH EVH1-binding motif. Our screen provides a way to uncover the effects of proteomic context on motif-mediated binding, revealing diverse mechanisms of control over EVH1 interactions and establishing that SLiMs can’t be fully understood outside of their native context. © Hwang et al.
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Except where otherwise noted, this item's license is described as Copyright Hwang et al. This article is distributed under the terms of the Creative Commons Attribution License.
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