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6au6

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Revision as of 05:52, 30 May 2018

Crystal structure of GDP-bound human GNAS R201C mutant

Structural highlights

6au6 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Gene:	GNAS, GNAS1, GSP (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[GNAS2_HUMAN] Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

[GNAS2_HUMAN] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Galphas. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Galphas through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-function mutation in Galphas that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Galphas bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Galphas can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins.

Disease-Causing Mutations in the G Protein Galphas Subvert the Roles of GDP and GTP.,Hu Q, Shokat KM Cell. 2018 Apr 1. pii: S0092-8674(18)30298-8. doi: 10.1016/j.cell.2018.03.018. PMID:29628140^[6]

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

References

↑ Pak Y, Pham N, Rotin D. Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Mol Cell Biol. 2002 Nov;22(22):7942-52. PMID:12391161
↑ Gao X, Sadana R, Dessauer CW, Patel TB. Conditional stimulation of type V and VI adenylyl cyclases by G protein betagamma subunits. J Biol Chem. 2007 Jan 5;282(1):294-302. Epub 2006 Nov 16. PMID:17110384 doi:http://dx.doi.org/10.1074/jbc.M607522200
↑ Thiele S, de Sanctis L, Werner R, Grotzinger J, Aydin C, Juppner H, Bastepe M, Hiort O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum Mutat. 2011 Jun;32(6):653-60. doi: 10.1002/humu.21489. Epub 2011 Apr 12. PMID:21488135 doi:http://dx.doi.org/10.1002/humu.21489
↑ Brand CS, Sadana R, Malik S, Smrcka AV, Dessauer CW. Adenylyl Cyclase 5 Regulation by Gbetagamma Involves Isoform-Specific Use of Multiple Interaction Sites. Mol Pharmacol. 2015 Oct;88(4):758-67. doi: 10.1124/mol.115.099556. Epub 2015 Jul , 23. PMID:26206488 doi:http://dx.doi.org/10.1124/mol.115.099556
↑ Farfel Z, Iiri T, Shapira H, Roitman A, Mouallem M, Bourne HR. Pseudohypoparathyroidism, a novel mutation in the betagamma-contact region of Gsalpha impairs receptor stimulation. J Biol Chem. 1996 Aug 16;271(33):19653-5. PMID:8702665
↑ Hu Q, Shokat KM. Disease-Causing Mutations in the G Protein Galphas Subvert the Roles of GDP and GTP. Cell. 2018 Apr 1. pii: S0092-8674(18)30298-8. doi: 10.1016/j.cell.2018.03.018. PMID:29628140 doi:http://dx.doi.org/10.1016/j.cell.2018.03.018

1 Structural highlights
2 Disease
3 Function
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/6au6"

@@ Line 3: / Line 3: @@
 <StructureSection load='6au6' size='340' side='right' caption='[[6au6]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6au6]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AU6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AU6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6au6]] is a 1 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=6AU6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AU6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GNAS, GNAS1, GSP ([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=6au6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6au6 OCA], [http://pdbe.org/6au6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6au6 RCSB], [http://www.ebi.ac.uk/pdbsum/6au6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6au6 ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Hu, Q]]
 [[Category: Shokat, K M]]

6au6

From Proteopedia

Revision as of 05:52, 30 May 2018

Crystal structure of GDP-bound human GNAS R201C mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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