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| | <StructureSection load='1py1' size='340' side='right'caption='[[1py1]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='1py1' size='340' side='right'caption='[[1py1]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1py1]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. The July 2009 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''beta-Secretase'' by David Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2009_7 10.2210/rcsb_pdb/mom_2009_7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PY1 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1PY1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1py1]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The July 2009 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''beta-Secretase'' by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2009_7 10.2210/rcsb_pdb/mom_2009_7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PY1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PY1 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GGA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1py1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1py1 OCA], [http://pdbe.org/1py1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1py1 RCSB], [http://www.ebi.ac.uk/pdbsum/1py1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1py1 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1py1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1py1 OCA], [https://pdbe.org/1py1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1py1 RCSB], [https://www.ebi.ac.uk/pdbsum/1py1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1py1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GGA1_HUMAN GGA1_HUMAN]] Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (AC-LL) motif.<ref>PMID:11301005</ref> [[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> | + | [https://www.uniprot.org/uniprot/GGA1_HUMAN GGA1_HUMAN] Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (AC-LL) motif.<ref>PMID:11301005</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/py/1py1_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/py/1py1_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | [[Category: RCSB PDB Molecule of the Month]] | | [[Category: RCSB PDB Molecule of the Month]] |
| | [[Category: Beta-Secretase]] | | [[Category: Beta-Secretase]] |
| - | [[Category: Zhang, X C]] | + | [[Category: Zhang XC]] |
| - | [[Category: Zhu, G]] | + | [[Category: Zhu G]] |
| - | [[Category: Beta-secretase]]
| + | |
| - | [[Category: Protein transport]]
| + | |
| - | [[Category: Protein-peptide complex]]
| + | |
| - | [[Category: Super helix]]
| + | |
| - | [[Category: Vhs domain of gga1]]
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| Structural highlights
Function
GGA1_HUMAN Plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules with a cytosolic acidic cluster-dileucine (AC-LL) motif.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Puertollano R, Randazzo PA, Presley JF, Hartnell LM, Bonifacino JS. The GGAs promote ARF-dependent recruitment of clathrin to the TGN. Cell. 2001 Apr 6;105(1):93-102. PMID:11301005
- ↑ He X, Zhu G, Koelsch G, Rodgers KK, Zhang XC, Tang J. Biochemical and structural characterization of the interaction of memapsin 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins. Biochemistry. 2003 Oct 28;42(42):12174-80. PMID:14567678 doi:10.1021/bi035199h
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