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Abstract:
SH3 domains constitute a family of protein-protein interaction modules
that bind to peptides displaying an X-proline-X-X-proline (XPXXP)
consensus. We report that the SH3 domain of Eps8, a substrate of
receptor and non-receptor tyrosine kinases, displays a novel and unique
binding preference. By a combination of approaches including (i)
screening of phage-displayed random peptide libraries, (ii) mapping of
the binding regions on three physiological interactors of Eps8, (iii)
alanine scanning of binding peptides and (iv) in vitro cross-linking, me
demonstrate that a proline-X-X-aspartate-tyrosine (PXXDY) consensus is
indispensable for binding to the SH3 domain of Eps8, Screening of the
Expressed Sequence Tags database allowed the identification of three
Eps8-related genes, whose SH3s also display unusual binding preferences
and constitute a phylogenetically distinct subfamily within the SH3
family, Thus, Eps8 identifies a novel family of SH3-containing proteins
that do not bind to canonical XPXXP-containing peptides, and that
establish distinct interactions in the signaling network.
