Structural determinants of substrate binding and activity regulation in leukemia- associated rho guanine-nucleotide exhcange factor (LARG)



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Rho guanine-nucleotide exchange factors (RhoGEFs) activate Rho GTPases, and regulate cell events including cytoskeletal structure, gene transcription, and cell migration. Leukemia-associated RhoGEF (LARG) belongs to a small subfamily of RhoGEFs that mediate the signal transduction from Gα12/13 to RhoA. Based on the atomic structures of the catalytic Dbl homology (DH) and pleckstrin homology (PH) domains of LARG alone, and in complex with RhoA, the residues responsible for interaction and catalysis were identified. The mutants of these residues were constructed in the context of the DH/PH, the RH/DH/PH domains and full-length LARG and were analyzed in in vitro and in vivo assays. A novel N-terminal extension of the DH domain and a hydrophobic patch of the PH domain were discovered and proven to be important in nucleotide exchange. Meanwhile, the structures of the DH/PH-RhoA-GDP complex and fragments of LARG were pursued.