Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase

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 membra...

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Autores principales:	Zhang, X., Cao, S., Barila, G., Edreira, M.M., Wankhede, M., Naim, N., Buck, M., Altschuler, D.L.
Formato:	JOUR
Materias:	Cell proliferation Chains Cytology Binding partners Biological response Computational approach Effector domains High affinity binding Membrane compartment Prenyl-binding proteins Side-chain interactions Proteins binding protein cyclase associated protein 1 lipid prenylamine Rap1 protein unclassified drug CAP1 protein, human cell cycle protein cytoskeleton protein diterpene geranylgeranic acid Rap protein RAP1B protein, human animal cell beta sheet binding affinity carboxy terminal sequence controlled study human human cell nonhuman priority journal protein binding protein domain protein prenylation protein protein interaction rat Review static electricity animal cell culture chemistry genetics metabolism molecular dynamics molecular model protein conformation thyroid follicular cell Animals Cell Cycle Proteins Cells, Cultured Cytoskeletal Proteins Diterpenes Humans Models, Molecular Molecular Dynamics Simulation Protein Conformation Protein Prenylation rap GTP-Binding Proteins Rats Thyroid Epithelial Cells
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00219258_v293_n20_p_Zhang
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	todo:paper_00219258_v293_n20_p_Zhang2023-10-03T14:23:25Z Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase Zhang, X. Cao, S. Barila, G. Edreira, M.M. Wankhede, M. Naim, N. Buck, M. Altschuler, D.L. Cell proliferation Chains Cytology Binding partners Biological response Computational approach Effector domains High affinity binding Membrane compartment Prenyl-binding proteins Side-chain interactions Proteins binding protein cyclase associated protein 1 lipid prenylamine Rap1 protein unclassified drug CAP1 protein, human cell cycle protein cytoskeleton protein diterpene geranylgeranic acid Rap protein RAP1B protein, human animal cell beta sheet binding affinity carboxy terminal sequence controlled study human human cell nonhuman priority journal protein binding protein domain protein prenylation protein protein interaction rat Review static electricity animal cell culture chemistry genetics metabolism molecular dynamics molecular model protein conformation protein prenylation thyroid follicular cell Animals Cell Cycle Proteins Cells, Cultured Cytoskeletal Proteins Diterpenes Humans Models, Molecular Molecular Dynamics Simulation Protein Conformation Protein Prenylation rap GTP-Binding Proteins Rats Thyroid Epithelial Cells 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 -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 -sheet domain. The binding was stabilized by the lipid insertion into the -solenoid whose interior was occupied by nonpolar side chains. This model was reminiscent of the recently solved structure of the PDE-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. © 2018 Zhang et al. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00219258_v293_n20_p_Zhang
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Cell proliferation Chains Cytology Binding partners Biological response Computational approach Effector domains High affinity binding Membrane compartment Prenyl-binding proteins Side-chain interactions Proteins binding protein cyclase associated protein 1 lipid prenylamine Rap1 protein unclassified drug CAP1 protein, human cell cycle protein cytoskeleton protein diterpene geranylgeranic acid Rap protein RAP1B protein, human animal cell beta sheet binding affinity carboxy terminal sequence controlled study human human cell nonhuman priority journal protein binding protein domain protein prenylation protein protein interaction rat Review static electricity animal cell culture chemistry genetics metabolism molecular dynamics molecular model protein conformation protein prenylation thyroid follicular cell Animals Cell Cycle Proteins Cells, Cultured Cytoskeletal Proteins Diterpenes Humans Models, Molecular Molecular Dynamics Simulation Protein Conformation Protein Prenylation rap GTP-Binding Proteins Rats Thyroid Epithelial Cells
spellingShingle	Cell proliferation Chains Cytology Binding partners Biological response Computational approach Effector domains High affinity binding Membrane compartment Prenyl-binding proteins Side-chain interactions Proteins binding protein cyclase associated protein 1 lipid prenylamine Rap1 protein unclassified drug CAP1 protein, human cell cycle protein cytoskeleton protein diterpene geranylgeranic acid Rap protein RAP1B protein, human animal cell beta sheet binding affinity carboxy terminal sequence controlled study human human cell nonhuman priority journal protein binding protein domain protein prenylation protein protein interaction rat Review static electricity animal cell culture chemistry genetics metabolism molecular dynamics molecular model protein conformation protein prenylation thyroid follicular cell Animals Cell Cycle Proteins Cells, Cultured Cytoskeletal Proteins Diterpenes Humans Models, Molecular Molecular Dynamics Simulation Protein Conformation Protein Prenylation rap GTP-Binding Proteins Rats Thyroid Epithelial Cells Zhang, X. Cao, S. Barila, G. Edreira, M.M. Wankhede, M. Naim, N. Buck, M. Altschuler, D.L. Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase
topic_facet	Cell proliferation Chains Cytology Binding partners Biological response Computational approach Effector domains High affinity binding Membrane compartment Prenyl-binding proteins Side-chain interactions Proteins binding protein cyclase associated protein 1 lipid prenylamine Rap1 protein unclassified drug CAP1 protein, human cell cycle protein cytoskeleton protein diterpene geranylgeranic acid Rap protein RAP1B protein, human animal cell beta sheet binding affinity carboxy terminal sequence controlled study human human cell nonhuman priority journal protein binding protein domain protein prenylation protein protein interaction rat Review static electricity animal cell culture chemistry genetics metabolism molecular dynamics molecular model protein conformation protein prenylation thyroid follicular cell Animals Cell Cycle Proteins Cells, Cultured Cytoskeletal Proteins Diterpenes Humans Models, Molecular Molecular Dynamics Simulation Protein Conformation Protein Prenylation rap GTP-Binding Proteins Rats Thyroid Epithelial Cells
description	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 -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 -sheet domain. The binding was stabilized by the lipid insertion into the -solenoid whose interior was occupied by nonpolar side chains. This model was reminiscent of the recently solved structure of the PDE-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. © 2018 Zhang et al.
format	JOUR
author	Zhang, X. Cao, S. Barila, G. Edreira, M.M. Wankhede, M. Naim, N. Buck, M. Altschuler, D.L.
author_facet	Zhang, X. Cao, S. Barila, G. Edreira, M.M. Wankhede, M. Naim, N. Buck, M. Altschuler, D.L.
author_sort	Zhang, X.
title	Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase
title_short	Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase
title_full	Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase
title_fullStr	Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase
title_full_unstemmed	Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase
title_sort	cyclase-associated protein 1 (cap1) is a prenyl-binding partner of rap1 gtpase
url	http://hdl.handle.net/20.500.12110/paper_00219258_v293_n20_p_Zhang
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_version_	1782025629443555328

Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase

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