rac regulates its effector phospholipase Cgamma2 through interaction with a split pleckstrin homology domain.

The Journal of Biological Chemistry
Claudia WalliserTom D Bunney

Abstract

Several isoforms of phospholipase C (PLC) are regulated through interactions with Ras superfamily GTPases, including Rac proteins. Interestingly, of two closely related PLCgamma isoforms, only PLCgamma(2) has previously been shown to be activated by Rac. Here, we explore the molecular basis of this interaction as well as the structural properties of PLCgamma(2) required for activation. Based on reconstitution experiments with isolated PLCgamma variants and Rac2, we show that an unusual pleckstrin homology (PH) domain, designated as the split PH domain (spPH), is both necessary and sufficient to effect activation of PLCgamma(2) by Rac2. We also demonstrate that Rac2 directly binds to PLCgamma(2) as well as to the isolated spPH of this isoform. Furthermore, through the use of NMR spectroscopy and mutational analysis, we determine the structure of spPH, define the structural features of spPH required for Rac interaction, and identify critical amino acid residues at the interaction interface. We further discuss parallels and differences between PLCgamma(1) and PLCgamma(2) and the implications of our findings for their respective signaling roles.

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Datasets Mentioned

BETA
ABB84466

Methods Mentioned

BETA
GTPases
PCR
NMR
transfection
surface plasmon resonance
biosensor
chip
GTPase
nucleotide exchange

Software Mentioned

NMRPipe
BiaEvaluation
PARALLHDG
TALOS
PROCHECK
ANSIG for OpenGL
CNS
EqCal
PyMol
NMRDraw

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The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.