7LXE

ENAH EVH1 domain bound to peptide from ABI1

Summary for 7LXE

• Entry DOI: 10.2210/pdb7lxe/pdb
• Descriptor: Protein enabled homolog,Abl interactor 1 (1 entity in total)
• Functional Keywords: complex, cytoskeleton, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 17173.95

Authors

Keating, A.E.,Grant, R.A.,Hwang, T.H. (deposition date: 2021-03-03, release date: 2022-01-19, Last modification date: 2023-10-18)

Primary citation

Hwang, T.,Parker, S.S.,Hill, S.M.,Grant, R.A.,Ilunga, M.W.,Sivaraman, V.,Mouneimne, G.,Keating, A.E.
Native proline-rich motifs exploit sequence context to target actin-remodeling Ena/VASP protein ENAH.
Elife, 11:-, 2022

PubMed Abstract: 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.

PubMed: 35076015
DOI: 10.7554/eLife.70680

Experimental method

X-RAY DIFFRACTION (1.88 Å)