Conformational change upon ligand binding and dynamics of the PDZ domain from leukemia-associated Rho guanine nucleotide exchange factor.

Protein Science : a Publication of the Protein Society
Jiangxin LiuYunyu Shi

Abstract

Leukemia-associated Rho guanine nucleotide exchange factor (LARG) is a RhoA-specific guanine nucleotide exchange factor (GEF) that can activate RhoA. The PDZ (PSD-95/Disc-large/ZO-1 homology) domain of LARG interacts with membrane receptors, which can relay extracellular signals to RhoA signal transduction pathways. Until now there is no structural and dynamic information about these interactions. Here we report the NMR structures of the LARG PDZ in the apo form and in complex with the plexin-B1 C-terminal octapeptide. Unobservable resonances of the residues in betaB/betaC and betaE/alphaB loops in apo state were observed in the complex state. A distinct region of the binding groove in the LARG PDZ was found to undergo conformational change compared with other PDZs. Analysis of the (15)N relaxation data using reduced spectral density mapping shows that the apo LARG PDZ (especially its ligand-binding groove) is flexible and exhibits internal motions on both picosecond to nanosecond and microsecond to millisecond timescales. Mutagenesis and thermodynamic studies indicate that the conformation of the betaB/betaC and betaE/alphaB loops affects the PDZ-peptide interaction. It is suggested that the conformational flexibility could fa...Continue Reading

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Citations

Aug 18, 2009·Journal of Biomolecular NMR·Michael A DurneyJohn A A Ladias
Nov 3, 2009·Molecular Pharmacology·Mohamed AittalebJohn J G Tesmer
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Dec 24, 2013·Pharmacology & Therapeutics·Lucyna Pomierny-ChamiołoMałgorzata Filip
Oct 30, 2021·Journal of Peptide Science : an Official Publication of the European Peptide Society·Yan LiCongBao Kang

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