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Publication Abstract from PubMed

SH3 domains are common protein binding modules. The target sequence of SH3 domains is usually a proline-rich motif (PRM) containing a minimal "PxxP" sequence. The mechanism of how different SH3 domains specifically choose their targets from vast PxxP-containing sequences is still not very clear, as many reported SH3/PRM interactions are weak and promiscuous. Here, we identified the binding of the SH3 domain of ASAP1 to the PRM of MICAL1 with a sub-muM binding affinity, and determined the crystal structure of ASAP1-SH3 and MICAL1-PRM complex. Our structural and biochemical analyses revealed that the target-binding pocket of ASAP1-SH3 contains two negatively charged patches to recognize the "xPx + Px+" sequence in MICAL1-PRM and consequently strengthen the interaction, differing from the typical SH3/PRM interaction. This unique PRM-binding pocket is also found in the SH3 domains of GTPase Regulator associated with focal adhesion kinase (GRAF) and Src kinase associated phosphoprotein 1 (SKAP1), which we named SH3(AGS). In addition, we searched the Swiss-Prot database and found ~130 proteins with the SH3(AGS)-binding PRM in silico. Finally, gene ontology analysis suggests that the strong interaction between the SH3(AGS)-containing proteins and their targets may play roles in actin cytoskeleton regulation and vesicle trafficking.

Crystal Structure of the SH3 Domain of ASAP1 in Complex with the Proline Rich Motif (PRM) of MICAL1 Reveals a Unique SH3/PRM Interaction Mode.,Jia X, Lin L, Xu S, Li L, Wei Z, Yu C, Niu F Int J Mol Sci. 2023 Jan 11;24(2):1414. doi: 10.3390/ijms24021414. PMID:36674928^[1]

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