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

Gosser, Yuying Q., Nomanbhoy, Tyzoon K., Aghazadeh, Behzad, Manor, Danny, Combs, Carolyn, Cerione, Richard A., Rosen, Michael K.·1997·Nature
DOI 10.1038/42961
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Abstract

The Rho GDP-dissociation inhibitors (GDIs) negatively regulate Rho-family GTPases. The inhibitory activity of GDI derives both from an ability to bind the carboxy-terminal isoprene of Rho family members and extract them from membranes, and from inhibition of GTPase cycling between the GTP- and GDP-bound states. 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 (M[r] 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 beta-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.

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Metadata

Authors
Gosser, Y. Q., Nomanbhoy, T. K., Aghazadeh, B., Manor, D., Combs, C., Cerione, R. A., & Rosen, M. K.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
1997-06-19
Volume
387
Issue
6635
Pages
814-819
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/42961
Cited by
140
References
1
Language
en
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CoChat. (2026). Citation check: C-terminal binding domain of Rho GDP-dissociation inhibitor directs N-terminal inhibitory peptide to GTPases. https://app.cochat.ai/papers/10.1038/42961
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Gosser, Y. Q., Nomanbhoy, T. K., Aghazadeh, B., Manor, D., Combs, C., Cerione, R. A., & Rosen, M. K. (1997). C-terminal binding domain of Rho GDP-dissociation inhibitor directs N-terminal inhibitory peptide to GTPases. Nature. https://doi.org/10.1038/42961