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| | ==VHS domain of human GGA1 complexed with C-terminal peptide from BACE== | | ==VHS domain of human GGA1 complexed with C-terminal peptide from BACE== |
| - | <StructureSection load='1ujj' size='340' side='right' caption='[[1ujj]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='1ujj' size='340' side='right'caption='[[1ujj]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1ujj]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UJJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1UJJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1ujj]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UJJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1UJJ FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jwf|1jwf]], [[1jwg|1jwg]], [[1ujk|1ujk]]</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ujj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ujj OCA], [http://pdbe.org/1ujj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ujj RCSB], [http://www.ebi.ac.uk/pdbsum/1ujj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1ujj 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=1ujj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ujj OCA], [https://pdbe.org/1ujj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ujj RCSB], [https://www.ebi.ac.uk/pdbsum/1ujj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ujj 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kametaka, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Kawasaki, M]] | + | [[Category: Kametaka S]] |
| - | [[Category: Shiba, T]] | + | [[Category: Kawasaki M]] |
| - | [[Category: Shibata, M]] | + | [[Category: Shiba T]] |
| - | [[Category: Uchiyama, Y]] | + | [[Category: Shibata M]] |
| - | [[Category: Waguri, S]] | + | [[Category: Uchiyama Y]] |
| - | [[Category: Wakatsuki, S]] | + | [[Category: Waguri S]] |
| - | [[Category: Adaptor protein]]
| + | [[Category: Wakatsuki S]] |
| - | [[Category: Protein transport]]
| + | |
| - | [[Category: Protein transport-hydrolase complex]]
| + | |
| - | [[Category: Protein-peptide complex]]
| + | |
| 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
BACE (beta-site amyloid precursor protein cleaving enzyme, beta-secretase) is a type-I membrane protein which functions as an aspartic protease in the production of beta-amyloid peptide, a causative agent of Alzheimer's disease. Its cytoplasmic tail has a characteristic acidic-cluster dileucine motif recognized by the VHS domain of adaptor proteins, GGAs (Golgi-localizing, gamma-adaptin ear homology domain, ARF-interacting). Here we show that BACE is colocalized with GGAs in the trans-Golgi network and peripheral structures, and phosphorylation of a serine residue in the cytoplasmic tail enhances interaction with the VHS domain of GGA1 by about threefold. The X-ray crystal structure of the complex between the GGA1-VHS domain and the BACE C-terminal peptide illustrates a similar recognition mechanism as mannose 6-phosphate receptors except that a glutamine residue closes in to fill the gap created by the shorter BACE peptide. The serine and lysine of the BACE peptide point their side chains towards the solvent. However, phosphorylation of the serine affects the lysine side chain and the peptide backbone, resulting in one additional hydrogen bond and a stronger electrostatic interaction with the VHS domain, hence the reversible increase in affinity.
Insights into the phosphoregulation of beta-secretase sorting signal by the VHS domain of GGA1.,Shiba T, Kametaka S, Kawasaki M, Shibata M, Waguri S, Uchiyama Y, Wakatsuki S Traffic. 2004 Jun;5(6):437-48. PMID:15117318[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
- ↑ Shiba T, Kametaka S, Kawasaki M, Shibata M, Waguri S, Uchiyama Y, Wakatsuki S. Insights into the phosphoregulation of beta-secretase sorting signal by the VHS domain of GGA1. Traffic. 2004 Jun;5(6):437-48. PMID:15117318 doi:10.1111/j.1600-0854.2004.00188.x
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