2ag9

From Proteopedia

(Difference between revisions)

Revision as of 10:28, 8 January 2015

Crystal Structure of the Y137S mutant of GM2-Activator Protein

Structural highlights

2ag9 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1g13, 1pub, 1pu5, 1tjj, 2ag4, 2ag2
Gene:	GM2A (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Disease

[SAP3_HUMAN] Defects in GM2A are the cause of GM2-gangliosidosis type AB (GM2GAB) [MIM:272750]; also known as Tay-Sachs disease AB variant. GM2-gangliosidosis is an autosomal recessive lysosomal storage disease marked by the accumulation of GM2 gangliosides in the neuronal cells. GM2GAB is characterized by GM2 gangliosides accumulation in the presence of both hexosaminidase A and B.^[1] ^[2] ^[3]

Function

[SAP3_HUMAN] The large binding pocket can accommodate several single chain phospholipids and fatty acids, GM2A also exhibits some calcium-independent phospholipase activity (By similarity). Binds gangliosides and stimulates ganglioside GM2 degradation. It stimulates only the breakdown of ganglioside GM2 and glycolipid GA2 by beta-hexosaminidase A. It extracts single GM2 molecules from membranes and presents them in soluble form to beta-hexosaminidase A for cleavage of N-acetyl-D-galactosamine and conversion to GM3.

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

GM2-activator protein (GM2AP) is a lysosomal lipid transfer protein with important biological roles in ganglioside catabolism, phospholipid metabolism, and T-cell activation. Previous studies of crystal structures of GM2AP complexed with the physiological ligand GM2 and platelet activating factor (PAF) have shown binding at two specific locations within the spacious apolar pocket and an ordering effect of endogenous resident lipids. To investigate the structural basis of phospholipid binding further, GM2AP was cocrystallized with phosphatidylcholine (PC), known to interact with GM2AP. Analysis of three crystal forms revealed binding of single chain lipids and fatty acids only and surprisingly not intact PC. The regions of best defined electron density are consistent with the presence of lyso-PC and oleic acid, which constitute deacylation products of PC. Their acyl tails are in stacking contact with shorter, less well-defined stretches of electron density that may represent resident fatty acids. The GM2AP associated hydrolytic activity that generates lyso-PC was further confirmed by mass spectrometry and enzymatic assays. In addition, we report the structures of (i) mutant Y137S, assessing the role of Tyr137 in lipid transfer via the hydrophobic cleft, and (ii) apo-mouse GM2AP, revealing a hydrophobic pocket with a constricted opening. Our structural results provide new insights into the biological functions of GM2AP. The combined effect of hydrolytic and lipid transfer properties has profound implications in cellular signaling.

Crystal structure analysis of phosphatidylcholine-GM2-activator product complexes: evidence for hydrolase activity.,Wright CS, Mi LZ, Lee S, Rastinejad F Biochemistry. 2005 Oct 18;44(41):13510-21. PMID:16216074^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schroder M, Schnabel D, Suzuki K, Sandhoff K. A mutation in the gene of a glycolipid-binding protein (GM2 activator) that causes GM2-gangliosidosis variant AB. FEBS Lett. 1991 Sep 23;290(1-2):1-3. PMID:1915858
↑ Schroder M, Schnabel D, Hurwitz R, Young E, Suzuki K, Sandhoff K. Molecular genetics of GM2-gangliosidosis AB variant: a novel mutation and expression in BHK cells. Hum Genet. 1993 Nov;92(5):437-40. PMID:8244332
↑ Schepers U, Glombitza G, Lemm T, Hoffmann A, Chabas A, Ozand P, Sandhoff K. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Am J Hum Genet. 1996 Nov;59(5):1048-56. PMID:8900233
↑ Wright CS, Mi LZ, Lee S, Rastinejad F. Crystal structure analysis of phosphatidylcholine-GM2-activator product complexes: evidence for hydrolase activity. Biochemistry. 2005 Oct 18;44(41):13510-21. PMID:16216074 doi:http://dx.doi.org/10.1021/bi050668w

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2ag9"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2ag9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AG9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2AG9 FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1g13|1g13]], [[1pub|1pub]], [[1pu5|1pu5]], [[1tjj|1tjj]], [[2ag4|2ag4]], [[2ag2|2ag2]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1g13|1g13]], [[1pub|1pub]], [[1pu5|1pu5]], [[1tjj|1tjj]], [[2ag4|2ag4]], [[2ag2|2ag2]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GM2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GM2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
-<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ag9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ag9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ag9 RCSB], [http://www.ebi.ac.uk/pdbsum/2ag9 PDBsum]</span></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=2ag9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ag9 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ag9 RCSB], [http://www.ebi.ac.uk/pdbsum/2ag9 PDBsum]</span></td></tr>
-<table>
+</table>
 == Disease ==
 [[http://www.uniprot.org/uniprot/SAP3_HUMAN SAP3_HUMAN]] Defects in GM2A are the cause of GM2-gangliosidosis type AB (GM2GAB) [MIM:[http://omim.org/entry/272750 272750]]; also known as Tay-Sachs disease AB variant. GM2-gangliosidosis is an autosomal recessive lysosomal storage disease marked by the accumulation of GM2 gangliosides in the neuronal cells. GM2GAB is characterized by GM2 gangliosides accumulation in the presence of both hexosaminidase A and B.<ref>PMID:1915858</ref> <ref>PMID:8244332</ref> <ref>PMID:8900233</ref>
@@ Line 35: / Line 35: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Lee, S.]]
+[[Category: Lee, S]]
-[[Category: Mi, L Z.]]
+[[Category: Mi, L Z]]
-[[Category: Rastinejad, F.]]
+[[Category: Rastinejad, F]]
-[[Category: Wright, C S.]]
+[[Category: Wright, C S]]
 [[Category: Lipid binding protein]]

2ag9

From Proteopedia

Revision as of 10:28, 8 January 2015

Crystal Structure of the Y137S mutant of GM2-Activator Protein

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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