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Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2018 May 18; Vol. 293 (20), pp. 7659-7673. Date of Electronic Publication: 2018 Apr 04. - Publication Year :
- 2018
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Abstract
- Rap1 proteins are members of the Ras subfamily of small GTPases involved in many biological responses, including adhesion, cell proliferation, and differentiation. Like all small GTPases, they work as molecular allosteric units that are active in signaling only when associated with the proper membrane compartment. Prenylation, occurring in the cytosol, is an enzymatic posttranslational event that anchors small GTPases at the membrane, and prenyl-binding proteins are needed to mask the cytoplasm-exposed lipid during transit to the target membrane. However, several of these proteins still await discovery. In this study, we report that cyclase-associated protein 1 (CAP1) binds Rap1. We found that this binding is GTP-independent, does not involve Rap1's effector domain, and is fully contained in its C-terminal hypervariable region (HVR). Furthermore, Rap1 prenylation was required for high-affinity interactions with CAP1 in a geranylgeranyl-specific manner. The prenyl binding specifically involved CAP1's C-terminal hydrophobic β-sheet domain. We present a combination of experimental and computational approaches, yielding a model whereby the high-affinity binding between Rap1 and CAP1 involves electrostatic and nonpolar side-chain interactions between Rap1's HVR residues, lipid, and CAP1 β-sheet domain. The binding was stabilized by the lipid insertion into the β-solenoid whose interior was occupied by nonpolar side chains. This model was reminiscent of the recently solved structure of the PDEδ-K-Ras complex; accordingly, disruptors of this complex, e.g. deltarasin, blocked the Rap1-CAP1 interaction. These findings indicate that CAP1 is a geranylgeranyl-binding partner of Rap1.<br /> (© 2018 Zhang et al.)
- Subjects :
- Animals
Cell Cycle Proteins chemistry
Cell Cycle Proteins genetics
Cells, Cultured
Cytoskeletal Proteins chemistry
Cytoskeletal Proteins genetics
Diterpenes chemistry
Humans
Models, Molecular
Molecular Dynamics Simulation
Protein Conformation
Rats
rap GTP-Binding Proteins chemistry
rap GTP-Binding Proteins genetics
Cell Cycle Proteins metabolism
Cytoskeletal Proteins metabolism
Diterpenes metabolism
Protein Prenylation
Thyroid Epithelial Cells metabolism
rap GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 293
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29618512
- Full Text :
- https://doi.org/10.1074/jbc.RA118.001779