Elaboration of the Homer1 Recognition Landscape Reveals Incomplete Divergence of Paralogous EVH1 Domains.

Short linear motifs bind to structurally conserved domains to mediate many protein interactions. Current definitions of motifs, using regular expressions, are over simplified and do not capture what is required for binding. Unbiased proteome interaction screens can refine these definitions. For EVH1 domains considered in this work, screening elucidated Homer1 binding requirements and revealed a residual overlap of specificity of two anciently diverged families, highlighting both opportunities and challenges of multi-specificity in domain-motif interactions.