Electrostatic Forces Mediate the Specificity of RHO GTPase-GDI Interactions.
Amino Acid Sequence
/ genetics
Guanine Nucleotide Dissociation Inhibitors
/ chemistry
Humans
Hydrophobic and Hydrophilic Interactions
/ drug effects
Kinetics
Prenylation
/ drug effects
Static Electricity
rac1 GTP-Binding Protein
/ chemistry
rho GTP-Binding Proteins
/ chemistry
rho-Specific Guanine Nucleotide Dissociation Inhibitors
/ chemistry
CDC42
G domain
RAC1
RAC2
RHOA
RHOGDI
electrostatic steering
geranylgeranyl
guanine nucleotide dissociation inhibitors
hypervariable region
liposomes
membrane extraction
polybasic motif
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
19 Nov 2021
19 Nov 2021
Historique:
received:
25
10
2021
revised:
15
11
2021
accepted:
16
11
2021
entrez:
27
11
2021
pubmed:
28
11
2021
medline:
18
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34830380
pii: ijms222212493
doi: 10.3390/ijms222212493
pmc: PMC8622166
pii:
doi:
Substances chimiques
Guanine Nucleotide Dissociation Inhibitors
0
rho-Specific Guanine Nucleotide Dissociation Inhibitors
0
rac1 GTP-Binding Protein
EC 3.6.5.2
rho GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : grant number: AH 92/8-1
Organisme : Federal Ministry of Education and Research
ID : grant numbers: 01GM1902C
Organisme : Deutsche Forschungsgemeinschaft
ID : grant number: IRTG 1902-p6
Organisme : the European Network on Noonan Syndrome and Related Disorders
ID : NSEuroNet: 01GM1621B
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