Fig. 1

Domain organization of CASKIN2 and structure features of its SH3 domain. a CASKIN2, unlike CASKIN1, cannot bind the CASK scaffolding protein due to the absence of a CASK interacting domain (CID). The CASKIN sequences diverge in a proline rich (P-rich region), ultimately ending with a conserved C-terminal sequence of unknown significance. b Sequence comparison of the CASKIN2 and CASKIN1 SH3 domains. Black dots indicate amide resonances that could not be assigned, characteristic of intermediate (μs-ms) motions. Secondary structure of the CASKIN2 SH3 domain is shown below its sequence. Six amino acids constituting the canonical binding cleft are colored. c Cα superposition of the ensemble of lowest energy structures submitted to the Protein Data Bank (PDB: 2KE9) d Among the six amino acids in a typical peptide binding cleft, position 1 (K290) and position 5 (R319) are non-canonical. e A survey of binding clefts from SH3 domains in the Protein Data Bank that vary from the typical compliment of aliphatic and aromatic amino acids exemplified by Abl (PDB: 1ABO). From the survey, SH3 domains are observed to bear substitutions at one or more of the six positions (indicated by shading)