title: Identification of a novel effector domain of BIN1 for cancer suppression.
abstract: Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest. We hypothesized that BIN1 contains a MYC-independent effector domain (MID) for cancer suppression. Because a functionally unique domain frequently contains a distinct structure, the human full-length BIN1 protein was subjected to limited trypsin digestion and the digested peptides were analyzed with Edman sequencing and mass spectrometry. We identified a trypsin-resistant peptide that corresponds to amino acids 146-268 of BIN1. It encompassed part of the BAR region, a putative effector region of BIN1. Computational analysis predicted that the peptide is very likely to exhibit coiled-coil motifs, implying a potential role for this region in sustaining the BIN1 structure and function. Like MBD-deleted BIN1, the trypsin-resistant peptide of BIN1 was predominantly present in the cytoplasm and was sufficient to inhibit cancer growth, regardless of dysregulated c-MYC activity. Our results suggest that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Greta L
authors.initials: GL
authors.lastname: Lundgaard
authors.forename: Natae E
authors.initials: NE
authors.lastname: Daniels
authors.forename: Slovénie
authors.initials: S
authors.lastname: Pyndiah
authors.forename: Erica K
authors.initials: EK
authors.lastname: Cassimere
authors.forename: Kazi M
authors.initials: KM
authors.lastname: Ahmed
authors.forename: Amélie
authors.initials: A
authors.lastname: Rodrigue
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kihara
authors.forename: Carol B
authors.initials: CB
authors.lastname: Post
authors.forename: Daitoku
authors.initials: D
authors.lastname: Sakamuro
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D013058:Mass Spectrometry; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014357:Trypsin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D014357:Trypsin