PDBsum entry 1muz

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Endocytosis/exocytosis PDB id
Protein chain
81 a.a. *
* Residue conservation analysis
PDB id:
Name: Endocytosis/exocytosis
Title: Nmr structure of the tumor suppressor bin1: alternative splicing in melanoma and interaction with c-myc
Structure: Myc box dependent interacting protein 1. Chain: a. Fragment: residues 513-593. Synonym: bin1, bridging integrator 1, amphiphysin-like protein, amphiphysin ii, box-dependent myc-interacting protein-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 20 models
Authors: A.Pineda-Lucena,C.H.Arrowsmith
Key ref:
A.Pineda-Lucena et al. (2005). A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants. J Mol Biol, 351, 182-194. PubMed id: 15992821 DOI: 10.1016/j.jmb.2005.05.046
24-Sep-02     Release date:   30-Sep-03    
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Protein chain
Pfam   ArchSchema ?
O00499  (BIN1_HUMAN) -  Myc box-dependent-interacting protein 1
593 a.a.
81 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)


DOI no: 10.1016/j.jmb.2005.05.046 J Mol Biol 351:182-194 (2005)
PubMed id: 15992821  
A structure-based model of the c-Myc/Bin1 protein interaction shows alternative splicing of Bin1 and c-Myc phosphorylation are key binding determinants.
A.Pineda-Lucena, C.S.Ho, D.Y.Mao, Y.Sheng, R.C.Laister, R.Muhandiram, Y.Lu, B.T.Seet, S.Katz, T.Szyperski, L.Z.Penn, C.H.Arrowsmith.
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.
  Selected figure(s)  
Figure 1.
Figure 1. Domain architecture of (a) c-Myc and (b) Bin1. Conserved regions of c-Myc are indicated as NTD (N-terminal domain), CTD (C-terminal domain), MB1 (Myc box 1), MB2 (Myc box 2), BR (basic region), HLH (helix-loop-helix), and LZ (leucine zipper). The Thr58 and Ser62 phosphorylation sites are indicated by P. The different Bin1 domains are indicated as BAR (Bin1/amphiphysin/RVS167), U1 (unknown-1), U2 (unknown-2), MBD (c-Myc binding domain), and SH3 (Src homology 3). The position of the original murine clone #99 is shown relative to the human Bin1 sequence (black bar). The tumor-specific exon 12A splicing event is depicted against the Bin1+13 primary structure. The SH3-binding motifs of c-Myc and Bin1 are underlined. The construct with the entire MBD domain deleted is designated as Bin1ΔMBD. The C-terminal Bin1 constructs used in this work are represented schematically as Bin1C−12A, which includes a discontinuous amino acid sequence (residues 270–303 and 347–482), encoding the MBD and SH3 domains, but lacking the 12A sequence (304–346), Bin1C+12A that includes, in addition to the MBD and SH3, the tumor-specific exon 12A sequence (270–482), Bin1CΔPxxP in which the PxxP in exon 12A has been deleted, Bin1C(SH3) that encodes only the SH3 domain (402–482) and Bin1 MBD that encodes the MBD (346–402) domain alone. Residue numbering used in this work is based on the Bin1(−10+12A) isoform (Genbank accession AAC23750.1).
Figure 5.
Figure 5. Solution structures of the (a) and (b) Bin1C(SH3)/c-Myc(55-68) complex and (c) and (d) the Bin1+12A intramolecular complex. (a) An ensemble of 20 superimposed NMR-derived structures of Bin1C(SH3) bound to the synthetic peptide c-Myc(55-68) (shown in red) and (c) ensemble structures of the 213 residue Bin1C+12A intramolecular complex. For clarity, only residues 305–311 (RKGPPVP) (green) and the SH3 domain of Bin1C+12A intramolecular complex are shown. The orientation of the proline-rich peptides is different in the two structures, reflecting the difference in the locations of the positively charged residues within each peptide sequence. The locations of the n-Src, RT, and distal loops of the SH3 domain are shown in (a). (b) and (d) Molecular surface representations of the Bin1C(SH3)/c-Myc(55-68) complex and the Bin1+12A intramolecular complex with positive and negative electrostatic potential colored blue and red, respectively. The bound peptide sequences (c-Myc and +12A) are shown above. The two positively charged residues of each SH3 binding region are shown in green. The conserved c-Myc residues, Thr58 and Ser62, are shown in light blue and yellow, respectively. See the text for discussion.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 351, 182-194) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19629135 E.K.Cassimere, S.Pyndiah, and D.Sakamuro (2009).
The c-MYC-interacting proapoptotic tumor suppressor BIN1 is a transcriptional target for E2F1 in response to DNA damage.
  Cell Death Differ, 16, 1641-1653.  
19211505 E.Kennah, A.Ringrose, L.L.Zhou, S.Esmailzadeh, H.Qian, M.W.Su, Y.Zhou, and X.Jiang (2009).
Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells.
  Blood, 113, 4646-4655.  
18930786 G.C.Prendergast, A.J.Muller, A.Ramalingam, and M.Y.Chang (2009).
BAR the door: cancer suppression by amphiphysin-like genes.
  Biochim Biophys Acta, 1795, 25-36.  
19633357 P.Fernando, J.S.Sandoz, W.Ding, Repentigny, S.Brunette, J.F.Kelly, R.Kothary, and L.A.Megeney (2009).
Bin1 SRC homology 3 domain acts as a scaffold for myofiber sarcomere assembly.
  J Biol Chem, 284, 27674-27686.  
16524918 G.Ren, P.Vajjhala, J.S.Lee, B.Winsor, and A.L.Munn (2006).
The BAR domain proteins: molding membranes in fission, fusion, and phagy.
  Microbiol Mol Biol Rev, 70, 37.  
16896652 M.A.Bakheit, T.Scholzen, J.S.Ahmed, and U.Seitzer (2006).
Molecular characterization of a Theileria lestoquardi gene encoding for immunogenic protein splice variants.
  Parasitol Res, 100, 161-170.  
16945552 N.Meyer, S.S.Kim, and L.Z.Penn (2006).
The Oscar-worthy role of Myc in apoptosis.
  Semin Cancer Biol, 16, 275-287.  
16938463 S.R.Hann (2006).
Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function.
  Semin Cancer Biol, 16, 288-302.  
16935524 V.H.Cowling, and M.D.Cole (2006).
Mechanism of transcriptional activation by the Myc oncoproteins.
  Semin Cancer Biol, 16, 242-252.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.