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 Ca2+-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 Ca2+-free and Ca2+-bound forms of ALG-2, as well as the complex with an Alix oligopeptide, have revealed a mechanism of Ca2+-dependent binding of ALG-2 to its target protein. Binding of Ca2+ to EF3 (third EF-hand) enables the side chain of Arg125, 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 Ca2+-dependent adaptor protein.
The mechanism of Ca2+-dependent recognition of Alix by ALG-2: insights from X-ray crystal structures
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Hironori Suzuki, Masato Kawasaki, Tatsutoshi Inuzuka, Mayumi Okumura, Takeshi Kakiuchi, Hideki Shibata, Soichi Wakatsuki, Masatoshi Maki; The mechanism of Ca2+-dependent recognition of Alix by ALG-2: insights from X-ray crystal structures. Biochem Soc Trans 1 February 2009; 37 (1): 190–194. doi: https://doi.org/10.1042/BST0370190
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