1py1

From Proteopedia

(Difference between revisions)

Revision as of 07:38, 9 December 2020

Complex of GGA1-VHS domain and beta-secretase C-terminal phosphopeptide

Structural highlights

1py1 is a 8 chain structure with sequence from Human. The July 2009 RCSB PDB Molecule of the Month feature on beta-Secretase by David Goodsell is 10.2210/rcsb_pdb/mom_2009_7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Gene:	GGA1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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] [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.^[2] ^[3]

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^[4]

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
↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ 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

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1py1"

@@ Line 1: / Line 1: @@
 ==Complex of GGA1-VHS domain and beta-secretase C-terminal phosphopeptide==
-<StructureSection load='1py1' size='340' side='right' caption='[[1py1]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+<StructureSection load='1py1' size='340' side='right'caption='[[1py1]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == 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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1PY1 FirstGlance]. <br>
+<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>
 </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>
 <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='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=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'>[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>
 </table>
 == Function ==
@@ Line 34: / Line 34: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: RCSB PDB Molecule of the Month]]
 [[Category: Beta-Secretase]]

1py1

From Proteopedia

Revision as of 07:38, 9 December 2020

Complex of GGA1-VHS domain and beta-secretase C-terminal phosphopeptide

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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