C-terminal binding domain of Rho GDP-dissociation inhibitor directs N-terminal inhibitory peptide to GTPases

Yuying Q. Gosser, Tyzoon K. Nomanbhoy, Behzad Aghazadeh, Danny Manor, Carolyn Combs, Richard A. Cerione and Michael K. Rosen ()
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Yuying Q. Gosser: *Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue
Tyzoon K. Nomanbhoy: Molecular and Cell Biology, Cornell University
Behzad Aghazadeh: *Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue
Danny Manor: Molecular and Cell Biology, Cornell University
Carolyn Combs: Molecular and Cell Biology, Cornell University
Richard A. Cerione: Molecular and Cell Biology, Cornell University
Michael K. Rosen: Correspondence and requests for materials should be addressed to M.K.R.

Nature, 1997, vol. 387, issue 6635, 814-819

Abstract: Abstract The Rho GDP-dissociation inhibitors (GDIs) negatively regulate Rho-family GTPases1,2. The inhibitory activity of GDI derives both from an ability to bind the carboxy-terminal isoprene of Rho family members and extract them from membranes3,4, and from inhibition of GTPase cycling between the GTP- and GDP-bound states4,5. Here we demonstrate that these binding and inhibitory functions of rhoGDI can be attributed to two structurally distinct regions of the protein. A carboxy-terminal folded domain of relative molecular mass 16,000 (Mr 16K) binds strongly to the Rho-family member Cdc42, yet has little effect on the rate of nucleotide dissociation from the GTPase. The solution structure of this domain shows a β-sandwich motif with a narrow hydrophobic cleft that binds isoprenes, and an exposed surface that interacts with the protein portion of Cdc42. The amino-terminal region of rhoGDI is unstructured in the absence of target and contributes little to binding, but is necessary to inhibit nucleotide dissociation from Cdc42. These results lead to a model of rhoGDI function in which the carboxy-terminal binding domain targets the amino-terminal inhibitory region to GTPases, resulting in membrane extraction and inhibition of nucleotide cycling.

Date: 1997
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DOI: 10.1038/42961

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