title: Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) is predicted to interact with its partner through an ARM-type α-helical structure.
abstract: BACKGROUND
  Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) has been identified recently as a novel regulator of estrogen signalling in breast cancer cells. Despite being a potential target for new breast cancer treatment, its amino acid sequence suggests no association with any well-characterized protein family and provides little clues as to its molecular function. In this paper, we predicted the structure, function and interactions of BIG3 using a range of bioinformatic tools.
  
  
  RESULTS
  Homology search results showed that BIG3 had distinct features from its paralogues, BIG1 and BIG2, with a unique region between the two shared domains, Sec7 and DUF1981. Although BIG3 contains Sec7 domain, the lack of the conserved motif and the critical glutamate residue suggested no potential guaninyl-exchange factor (GEF) activity. Fold recognition tools predicted BIG3 to adopt an α-helical repeat structure similar to that of the armadillo (ARM) family. Using state-of-the-art methods, we predicted interaction sites between BIG3 and its partner PHB2.
  
  
  CONCLUSIONS
  The combined results of the structure and interaction prediction led to a novel hypothesis that one of the predicted helices of BIG3 might play an important role in binding to PHB2 and thereby preventing its translocation to the nucleus. This hypothesis has been subsequently verified experimentally.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Chen
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Murakami
authors.forename: Shandar
authors.initials: S
authors.lastname: Ahmad
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
authors.affiliation: National Institute of Biomedical Innovation, 7-6-8 Saito-asagi, Ibaraki city, Osaka 567-0085, Japan. kenji@nibio.go.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Mizuguchi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000091402:Prohibitins; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: C000595370:ARFGEF3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012097:Repressor Proteins