1x86
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Crystal Structure of the DH/PH domains of Leukemia-associated RhoGEF in complex with RhoA
OverviewOverview
Rho guanine-nucleotide exchange factors (RhoGEFs) activate Rho GTPases, and thereby regulate cytoskeletal structure, gene transcription, and cell, migration. Leukemia-associated RhoGEF (LARG) belongs to a small subfamily, of RhoGEFs that are RhoA-selective and directly activated by the, Galpha12/13 family of heterotrimeric G proteins. Herein we describe the, atomic structures of the catalytic Dbl homology (DH) and pleckstrin, homology (PH) domains of LARG alone and in complex with RhoA. These, structures demonstrate that the DH/PH domains of LARG can undergo a, dramatic conformational change upon binding RhoA, wherein both the DH and, PH domains directly engage RhoA. Through mutational analysis we show that, full nucleotide exchange activity requires a novel N-terminal extension on, the DH domain that is predicted to exist in a broader family of RhoGEFs, that includes p115-RhoGEF, Lbc, Lfc, Net1, and Xpln, and identify regions, within the LARG PH domain that contribute to its ability to facilitate, nucleotide exchange in vitro. In crystals of the DH/PH-RhoA complex, the, active site of RhoA adopts two distinct GDP-excluding conformations among, the four unique complexes in the asymmetric unit. Similar changes were, previously observed in structures of nucleotide-free Ras and Ef-Tu. A, potential protein-docking site on the LARG PH domain is also evident and, appears to be conserved throughout the Lbc subfamily of RhoGEFs.
DiseaseDisease
Known diseases associated with this structure: Leukemia, acute myeloid OMIM:[604763]
About this StructureAbout this Structure
1X86 is a Protein complex structure of sequences from Homo sapiens with PO4 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor., Kristelly R, Gao G, Tesmer JJ, J Biol Chem. 2004 Nov 5;279(45):47352-62. Epub 2004 Aug 25. PMID:15331592
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