A Structure-based Model of the c-Myc/Bin1 Protein Interaction Shows Alternative Splicing of Bin1 and c-Myc Phosphorylation are Key Binding Determinants

• Published in: Journal of molecular biology 2005-08, Vol.351 (1), p.182-194
• Main Authors: Pineda-Lucena, Antonio, Ho, Cynthia S.W., Mao, Daniel Y.L., Sheng, Yi, Laister, Rob C., Muhandiram, Ranjith, Lu, Ying, Seet, Bruce T., Katz, Sigal, Szyperski, Thomas, Penn, Linda Z., Arrowsmith, Cheryl H.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Alternative Splicing; Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Humans; intramolecular interaction; Models, Molecular; Neoplasm Proteins - chemistry; Neoplasm Proteins - metabolism; NMR structure; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; oncoprotein; Phosphorylation; Protein Binding; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Proto-Oncogene Proteins c-myc - chemistry; Proto-Oncogene Proteins c-myc - metabolism; src Homology Domains; tumor suppressor; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2005.05.046

The N terminus of the c-Myc oncoprotein interacts with Bin1, a ubiquitously expressed nucleocytoplasmic protein with features of a tumor suppressor. The c-Myc/Bin1 interaction is dependent on the highly conserved Myc Box 1 (MB1) sequence of c-Myc. The c-Myc/Bin1 interaction has potential regulatory significance as c-Myc-mediated transformation and apoptosis can be modulated by the expression of Bin1. Multiple splicing of the Bin1 transcript results in ubiquitous, tissue-specific and tumor-specific populations of Bin1 proteins in vivo. We report on the structural features of the interaction between c-Myc and Bin1, and describe two mechanisms by which the binding of different Bin1 isoforms to c-Myc may be regulated in cells. Our findings identify a consensus class II SH3-binding motif in c-Myc and the C-terminal SH3 domain of Bin1 as the primary structure determinants of their interaction. We present biochemical and structural evidence that tumor-specific isoforms of Bin1 are precluded from interaction with c-Myc through an intramolecular polyproline–SH3 domain interaction that inhibits the Bin1 SH3 domain from binding to c-Myc. Furthermore, c-Myc/Bin1 interaction can be inhibited by phosphorylation of c-Myc at Ser62, a functionally important residue found within the c-Myc SH3-binding motif. Our data provide a structure-based model of the c-Myc/Bin1 interaction and suggest a mode of regulation that may be important for c-Myc function as a regulator of gene transcription.