1py1
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Complex of GGA1-VHS domain and beta-secretase C-terminal phosphopeptide
OverviewOverview
Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease, that initiates the hydrolysis of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta and the onset of Alzheimer's, disease (AD). Both memapsin 2 and APP are transported from the cell, surface to endosomes where APP hydrolysis takes place. Thus, the, intracellular transport mechanism of memapsin 2 is important for, understanding the pathogenesis of AD. We have previously shown that the, cytosolic domain of memapsin 2 contains an acid-cluster-dileucine (ACDL), motif that binds the VHS domain of GGA proteins (He et al. (2002) FEBS, Lett. 524, 183-187). This mechanism is the presumed recognition step for, the vesicular packaging of memapsin 2 for its transport to endosomes. The, phosphorylation of a serine residue within the ACDL motif has been, reported to regulate the recycling of memapsin 2 from early endosomes back, to the cell surface. Here, we report a study on the memapsin 2/VHS domain, interaction. Using isothermal titration calorimetry, the dissociation, constant, K(d), values are 4.0 x 10(-4), 4.1 x 10(-4), and 3.1 x 10(-4) M, for VHS domains from GGA1, GGA2, and GGA3, respectively. With the serine, residue replaced by phosphoserine, the K(d) decreased about 10-, 4-, and, 14-fold for the same three VHS domains. A crystal structure of the complex, between memapsin 2 phosphoserine peptide and GGA1 VHS was solved at 2.6 A, resolution. The side chain of the phosphoserine group does not interact, with the VHS domain but forms an ionic interaction with the side chain of, the C-terminal lysine of the ligand peptide. Energy calculation of the, binding of native and phosphorylated peptides to VHS domains suggests that, this intrapeptide ionic bond in solution may reduce the change in binding, entropy and thus increase binding affinity.
About this StructureAbout this Structure
1PY1 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins., He X, Zhu G, Koelsch G, Rodgers KK, Zhang XC, Tang J, Biochemistry. 2003 Oct 28;42(42):12174-80. PMID:14567678
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