3sea

From Proteopedia

(Difference between revisions)

Revision as of 22:40, 25 December 2014

Structure of Rheb-Y35A mutant in GDP- and GMPPNP-bound forms

Structural highlights

3sea 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:	1xtr, 1xts, 1xtq, 2l0x, 3oes
Gene:	RHEB, RHEB2 (Homo sapiens)
Resources:	FirstGlance, OCA, RCSB, PDBsum

Function

[RHEB_HUMAN] Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Activates the protein kinase activity of mTORC1. Has low intrinsic GTPase activity.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Rheb, an activator of mammalian target of rapamycin (mTOR), displays low intrinsic GTPase activity favoring the biologically activated, GTP-bound state. We identified a Rheb mutation (Y35A) that increases its intrinsic nucleotide hydrolysis activity approximately 10-fold, and solved structures of both its active and inactive forms, revealing an unexpected mechanism of GTP hydrolysis involving Asp65 in switch II and Thr38 in switch I. In the wild-type protein this noncanonical mechanism is markedly inhibited by Tyr35, which constrains the active site conformation, restricting the access of the catalytic Asp65 to the nucleotide-binding pocket. Rheb Y35A mimics the enthalpic and entropic changes associated with GTP hydrolysis elicited by the GTPase-activating protein (GAP) TSC2, and is insensitive to further TSC2 stimulation. Overexpression of Rheb Y35A impaired the regulation of mTORC1 signaling by growth factor availability. We demonstrate that the opposing functions of Tyr35 in the intrinsic and GAP-stimulated GTP catalysis are critical for optimal mTORC1 regulation.

An Autoinhibited Noncanonical Mechanism of GTP Hydrolysis by Rheb Maintains mTORC1 Homeostasis.,Mazhab-Jafari MT, Marshall CB, Ishiyama N, Ho J, Di Palma V, Stambolic V, Ikura M Structure. 2012 Jul 19. PMID:22819219^[7]

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

References

↑ Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13571-6. Epub 2002 Sep 23. PMID:12271141 doi:10.1073/pnas.202476899
↑ Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003 Aug 1;17(15):1829-34. Epub 2003 Jul 17. PMID:12869586 doi:10.1101/gad.1110003
↑ Li Y, Inoki K, Guan KL. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol. 2004 Sep;24(18):7965-75. PMID:15340059 doi:10.1128/MCB.24.18.7965-7975.2004
↑ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol. 2005 Apr 26;15(8):702-13. PMID:15854902 doi:S0960-9822(05)00226-5
↑ Tee AR, Blenis J, Proud CG. Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1. FEBS Lett. 2005 Aug 29;579(21):4763-8. PMID:16098514 doi:10.1016/j.febslet.2005.07.054
↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
↑ Mazhab-Jafari MT, Marshall CB, Ishiyama N, Ho J, Di Palma V, Stambolic V, Ikura M. An Autoinhibited Noncanonical Mechanism of GTP Hydrolysis by Rheb Maintains mTORC1 Homeostasis. Structure. 2012 Jul 19. PMID:22819219 doi:10.1016/j.str.2012.06.013

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3sea"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[3sea]] 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=3SEA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SEA FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1xtr|1xtr]], [[1xts|1xts]], [[1xtq|1xtq]], [[2l0x|2l0x]], [[3oes|3oes]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1xtr|1xtr]], [[1xts|1xts]], [[1xtq|1xtq]], [[2l0x|2l0x]], [[3oes|3oes]]</td></tr>
-<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RHEB, RHEB2 ([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">RHEB, RHEB2 ([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=3sea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sea OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sea RCSB], [http://www.ebi.ac.uk/pdbsum/3sea 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=3sea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sea OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3sea RCSB], [http://www.ebi.ac.uk/pdbsum/3sea PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/RHEB_HUMAN RHEB_HUMAN]] Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Activates the protein kinase activity of mTORC1. Has low intrinsic GTPase activity.<ref>PMID:12271141</ref> <ref>PMID:12869586</ref> <ref>PMID:15340059</ref> <ref>PMID:15854902</ref> <ref>PMID:16098514</ref> <ref>PMID:20381137</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 26: @@
 </StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Ikura, M.]]
+[[Category: Ikura, M]]
-[[Category: Ishiyama, N.]]
+[[Category: Ishiyama, N]]
-[[Category: Marshall, C B.]]
+[[Category: Marshall, C B]]
-[[Category: Mazhab-Jafari, M T.]]
+[[Category: Mazhab-Jafari, M T]]
-[[Category: Vuk, S.]]
+[[Category: Vuk, S]]
 [[Category: Globular]]
 [[Category: Hydrolase]]

3sea

From Proteopedia

Revision as of 22:40, 25 December 2014

Structure of Rheb-Y35A mutant in GDP- and GMPPNP-bound forms

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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