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Publication Abstract from PubMed

The 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.

Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH.,Hwang T, Parker SS, Hill SM, Grant RA, Ilunga MW, Sivaraman V, Mouneimne G, Keating AE Elife. 2022 Jan 25;11. pii: 70680. doi: 10.7554/eLife.70680. PMID:35076015^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.