Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions

Three decades of research have documented the spatiotemporal dynamics of RHO family GTPase membrane extraction regulated by guanine nucleotide dissociation inhibitors (GDIs), but the interplay of the kinetic mechanism and structural specificity of these interactions is as yet unresolved. To address...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Niloufar Mosaddeghzadeh, Neda S. Kazemein Jasemi, Jisca Majolée, Si-Cai Zhang, Peter L. Hordijk, Radovan Dvorsky, Mohammad Reza Ahmadian
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CDC42 electrostatic steering G domain hypervariable region geranylgeranyl guanine nucleotide dissociation inhibitors Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/016abdbc02aa459eb551752890f5a0da
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:016abdbc02aa459eb551752890f5a0da
record_format	dspace
spelling	oai:doaj.org-article:016abdbc02aa459eb551752890f5a0da2021-11-25T17:57:16ZElectrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions10.3390/ijms2222124931422-00671661-6596https://doaj.org/article/016abdbc02aa459eb551752890f5a0da2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12493https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Three decades of research have documented the spatiotemporal dynamics of RHO family GTPase membrane extraction regulated by guanine nucleotide dissociation inhibitors (GDIs), but the interplay of the kinetic mechanism and structural specificity of these interactions is as yet unresolved. To address this, we reconstituted the GDI-controlled spatial segregation of geranylgeranylated RHO protein RAC1 in vitro. Various biochemical and biophysical measurements provided unprecedented mechanistic details for GDI function with respect to RHO protein dynamics. We determined that membrane extraction of RHO GTPases by GDI occurs via a 3-step mechanism: (1) GDI non-specifically associates with the switch regions of the RHO GTPases; (2) an electrostatic switch determines the interaction specificity between the C-terminal polybasic region of RHO GTPases and two distinct negatively-charged clusters of GDI1; (3) a non-specific displacement of geranylgeranyl moiety from the membrane sequesters it into a hydrophobic cleft, effectively shielding it from the aqueous milieu. This study substantially extends the model for the mechanism of GDI-regulated RHO GTPase extraction from the membrane, and could have implications for clinical studies and drug development.Niloufar MosaddeghzadehNeda S. Kazemein JasemiJisca MajoléeSi-Cai ZhangPeter L. HordijkRadovan DvorskyMohammad Reza AhmadianMDPI AGarticleCDC42electrostatic steeringG domainhypervariable regiongeranylgeranylguanine nucleotide dissociation inhibitorsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12493, p 12493 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CDC42 electrostatic steering G domain hypervariable region geranylgeranyl guanine nucleotide dissociation inhibitors Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	CDC42 electrostatic steering G domain hypervariable region geranylgeranyl guanine nucleotide dissociation inhibitors Biology (General) QH301-705.5 Chemistry QD1-999 Niloufar Mosaddeghzadeh Neda S. Kazemein Jasemi Jisca Majolée Si-Cai Zhang Peter L. Hordijk Radovan Dvorsky Mohammad Reza Ahmadian Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions
description	Three decades of research have documented the spatiotemporal dynamics of RHO family GTPase membrane extraction regulated by guanine nucleotide dissociation inhibitors (GDIs), but the interplay of the kinetic mechanism and structural specificity of these interactions is as yet unresolved. To address this, we reconstituted the GDI-controlled spatial segregation of geranylgeranylated RHO protein RAC1 in vitro. Various biochemical and biophysical measurements provided unprecedented mechanistic details for GDI function with respect to RHO protein dynamics. We determined that membrane extraction of RHO GTPases by GDI occurs via a 3-step mechanism: (1) GDI non-specifically associates with the switch regions of the RHO GTPases; (2) an electrostatic switch determines the interaction specificity between the C-terminal polybasic region of RHO GTPases and two distinct negatively-charged clusters of GDI1; (3) a non-specific displacement of geranylgeranyl moiety from the membrane sequesters it into a hydrophobic cleft, effectively shielding it from the aqueous milieu. This study substantially extends the model for the mechanism of GDI-regulated RHO GTPase extraction from the membrane, and could have implications for clinical studies and drug development.
format	article
author	Niloufar Mosaddeghzadeh Neda S. Kazemein Jasemi Jisca Majolée Si-Cai Zhang Peter L. Hordijk Radovan Dvorsky Mohammad Reza Ahmadian
author_facet	Niloufar Mosaddeghzadeh Neda S. Kazemein Jasemi Jisca Majolée Si-Cai Zhang Peter L. Hordijk Radovan Dvorsky Mohammad Reza Ahmadian
author_sort	Niloufar Mosaddeghzadeh
title	Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions
title_short	Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions
title_full	Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions
title_fullStr	Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions
title_full_unstemmed	Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions
title_sort	electrostatic forces mediate the specificity of rho gtpase-gdi interactions
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/016abdbc02aa459eb551752890f5a0da
work_keys_str_mv	AT niloufarmosaddeghzadeh electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions AT nedaskazemeinjasemi electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions AT jiscamajolee electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions AT sicaizhang electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions AT peterlhordijk electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions AT radovandvorsky electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions AT mohammadrezaahmadian electrostaticforcesmediatethespecificityofrhogtpasegdiinteractions
_version_	1718411780919656448

Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions

Ejemplares similares