Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions

Autor:	Mosaddeghzadeh, Niloufar, Kazemein Jasemi, Neda S., Majolée, Jisca, Zhang, Si-Cai, Hordijk, Peter L., Dvorsky, Radovan, Ahmadian, Mohammad Reza
Přispěvatelé:	VU University medical center, ACS - Microcirculation, Physiology
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	liposomes rac1 GTP-Binding Protein rho GTP-Binding Proteins membrane extraction QH301-705.5 Static Electricity electrostatic steering Article guanine nucleotide dissociation inhibitors geranylgeranyl Humans rho-Specific Guanine Nucleotide Dissociation Inhibitors G domain Amino Acid Sequence Biology (General) QD1-999 polybasic motif Prenylation CDC42 RHOA hypervariable region Chemistry Kinetics RHOGDI Hydrophobic and Hydrophilic Interactions RAC1 RAC2
Zdroj:	International Journal of Molecular Sciences Mosaddeghzadeh, N, Kazemein Jasemi, N S, Majolée, J, Zhang, S-C, Hordijk, P L, Dvorsky, R & Ahmadian, M R 2021, ' Electrostatic forces mediate the specificity of RHO GTPase-GDI interactions ', International Journal of Molecular Sciences, vol. 22, no. 22, 12493 . https://doi.org/10.3390/ijms222212493 Volume 22 Issue 22 International Journal of Molecular Sciences, Vol 22, Iss 12493, p 12493 (2021) International Journal of Molecular Sciences, 22(22):12493. Multidisciplinary Digital Publishing Institute (MDPI)
ISSN:	1422-0067 1661-6596
DOI:	10.3390/ijms222212493
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::1e37eb29ae1e130b2df224328645f979 http://europepmc.org/articles/PMC8622166 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.