C-terminal binding domain of Rho GDP-dissociation inhibitor directs N- terminal inhibitory peptide to GTPases Journal Article
| Authors: | Gosser, Y. Q.; Nomanbhoy, T. K.; Aghazadeh, B.; Manor, D.; Combs, C.; Cerione, R. A.; Rosen, M. K. |
| Article Title: | C-terminal binding domain of Rho GDP-dissociation inhibitor directs N- terminal inhibitory peptide to GTPases |
| 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 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. |
| Keywords: | binding affinity; protein conformation; animals; cell cycle proteins; carboxy terminal sequence; protein binding; gtp-binding proteins; regulatory mechanism; amino acid sequence; molecular sequence data; sequence alignment; magnetic resonance spectroscopy; binding site; hydrogen bonding; models, molecular; thermodynamics; protein structure, tertiary; cattle; protein folding; protein structure; structure analysis; molecular weight; protein structure, secondary; nuclear magnetic resonance; gtp phosphohydrolases; guanosine diphosphate; guanosine triphosphatase; protein isoprenylation; guanine nucleotide dissociation inhibitors; humans; priority journal; article; anthranilic acids; cdc42 gtp-binding protein, saccharomyces cerevisiae |
| Journal Title: | Nature |
| Volume: | 387 |
| Issue: | 6635 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1997-06-19 |
| Start Page: | 814 |
| End Page: | 819 |
| Language: | English |
| DOI: | 10.1038/42961 |
| PUBMED: | 9194563 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
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