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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

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...

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Detalles Bibliográficos
Autores principales: Jia, Xuanyan, Lin, Leishu, Xu, Shun, Li, Lingxuan, Wei, Zhiyi, Yu, Cong, Niu, Fengfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865144/
https://www.ncbi.nlm.nih.gov/pubmed/36674928
http://dx.doi.org/10.3390/ijms24021414
Descripción
Sumario: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-μM 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.