title: The mechanism of Ca2+-dependent recognition of Alix by ALG-2: insights from X-ray crystal structures.
abstract: Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X] was originally identified as a protein that interacts with ALG-2, a member of the penta-EF-hand Ca(2+)-binding protein family. ALG-2 binds to its C-terminal proline-rich region that contains four tandem repeats of PXY (where X represents an uncharged amino acid). Recent X-ray crystal structural analyses of the Ca(2+)-free and Ca(2+)-bound forms of ALG-2, as well as the complex with an Alix oligopeptide, have revealed a mechanism of Ca(2+)-dependent binding of ALG-2 to its target protein. Binding of Ca(2+) to EF3 (third EF-hand) enables the side chain of Arg(125), present in the loop connecting EF3 and EF4 (fourth EF-hand), to move sufficiently to make a primary hydrophobic pocket accessible to the critical PPYP (Pro-Pro-Tyr-Pro) motif in Alix, which partially overlaps with the GPP (Gly-Pro-Pro) motif for binding to Cep55 (centrosome protein of 55 kDa). The fact that ALG-2 forms a homodimer and each monomer has one peptide-binding site indicates the possibility that ALG-2 bridges two interacting proteins, including Alix and Tsg101 (tumour susceptibility gene 101), and functions as a Ca(2+)-dependent adaptor protein.
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masato
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Inuzuka
authors.forename: Mayumi
authors.initials: M
authors.lastname: Okumura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Shibata
authors.forename: Soichi
authors.initials: S
authors.lastname: Wakatsuki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Maki
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020832:EF Hand Motifs; D006801:Humans; D010455:Peptides / Q000737:chemistry
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; C097753:PDCD6 protein, human; D010455:Peptides; D002118:Calcium