Journal
STRUCTURE
Volume 12, Issue 11, Pages 1955-1965Publisher
CELL PRESS
DOI: 10.1016/j.str.2004.09.003
Keywords
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Funding
- NHLBI NIH HHS [P01 HL48807] Funding Source: Medline
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Calcium sensitization in smooth muscle is mediated by the RhoA GTPase, activated by hitherto unspecified nucleoticle exchange factors (GEFs) acting downstream of Galphaq/Galpha(12/13) trimeric G proteins. Here, we show that at least one potential GEF, the PDZRhoGEF, is present in smooth muscle, and its isolated DH/PH fragment induces calcium sensitization in the absence of agonist-mediated signaling. In vitro, the fragment shows high selectivity for the RhoA GTPase. Full-length fragment is required for the nucleotide exchange, as the isolated DH domain enhances it only marginally. We crystallized the DH/PH fragment of PDZRhoGEF in complex with nonprenylated human RhoA and determined the structure at 2.5 Angstrom resolution. The refined molecular model reveals that the mutual disposition of the DH and PH domains is significantly different from other previously described complexes involving DH/PH tandems, and that the PH domain interacts with RhoA in a unique mode. The DH domain makes several specific interactions with RhoA residues not conserved among other Rho family members, suggesting the molecular basis for the observed specificity.
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