View source for 6s6a


==Crystal structure of RagA-Q66L/RagC-T90N GTPase heterodimer complex==
<StructureSection load='6s6a' size='340' side='right'caption='[[6s6a]], [[Resolution|resolution]] 2.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6s6a]] is a 4 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=6S6A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S6A FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9JE:pentane-1,5-diol'>9JE</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</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">RRAGA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), RRAGC ([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=6s6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s6a OCA], [http://pdbe.org/6s6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s6a RCSB], [http://www.ebi.ac.uk/pdbsum/6s6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s6a ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/RRAGA_HUMAN RRAGA_HUMAN]] Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form. In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway. May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death. May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions, thereby affecting cell death.<ref>PMID:20381137</ref> <ref>PMID:25936802</ref> <ref>PMID:8995684</ref> <ref>PMID:9394008</ref>  [[http://www.uniprot.org/uniprot/RRAGC_HUMAN RRAGC_HUMAN]] Guanine nucleotide-binding protein forming heterodimeric Rag complexes required for the amino acid-induced relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. This is a crucial step in the activation of the TOR signaling cascade by amino acids.<ref>PMID:20381137</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagAGTP/RagCGDP nucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.

Architecture of human Rag GTPase heterodimers and their complex with mTORC1.,Anandapadamanaban M, Masson GR, Perisic O, Berndt A, Kaufman J, Johnson CM, Santhanam B, Rogala KB, Sabatini DM, Williams RL Science. 2019 Oct 11;366(6462):203-210. doi: 10.1126/science.aax3939. PMID:31601764<ref>PMID:31601764</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6s6a" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Anandapadamanaban, M]]
[[Category: Kaufman, J]]
[[Category: Masson, G R]]
[[Category: Perisic, O]]
[[Category: Williams, R L]]
[[Category: Gtpase domain]]
[[Category: Mtorc1 activator]]
[[Category: Roadblock domain]]
[[Category: Signaling protein]]
[[Category: Small gtpase]]