Molecular basis for activation and biased signaling at the thrombin-activated GPCR proteinase activated receptor-4 (PAR4).
Alanine
/ genetics
Amino Acid Substitution
Calcium
/ metabolism
Calcium Signaling
GTP-Binding Protein alpha Subunits, Gq-G11
/ metabolism
HEK293 Cells
Humans
Isomerism
MAP Kinase Signaling System
Methylation
Molecular Docking Simulation
Mutant Proteins
/ metabolism
Mutation
/ genetics
Peptides
/ metabolism
Phosphorylation
Platelet Aggregation
Receptors, Thrombin
/ agonists
Signal Transduction
Structural Homology, Protein
Thrombin
/ metabolism
beta-Arrestins
/ metabolism
G-protein
G-protein–coupled receptor (GPCR)
arrestin
biased signaling
bioluminescence
bioluminescence resonance energy transfer (BRET)
docking
mitogen-activated protein kinase (MAPK)
peptide
platelet
protease-activated receptor-4 (PAR4)
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
21 02 2020
21 02 2020
Historique:
received:
11
10
2019
revised:
28
12
2019
pubmed:
2
1
2020
medline:
21
10
2020
entrez:
2
1
2020
Statut:
ppublish
Résumé
Proteinase-activated receptor (PAR)-4 is a member of the proteolytically-activated PAR family of G-protein-coupled receptors (GPCR) that represents an important target in the development of anti-platelet therapeutics. PARs are activated by proteolytic cleavage of their receptor N terminus by enzymes such as thrombin, trypsin, and cathepsin-G. This reveals the receptor-activating motif, termed the tethered ligand that binds intramolecularly to the receptor and triggers signaling. However, PARs are also activated by exogenous application of synthetic peptides derived from the tethered-ligand sequence. To better understand the molecular basis for PAR4-dependent signaling, we examined PAR4-signaling responses to a peptide library derived from the canonical PAR4-agonist peptide, AYPGKF-NH
Identifiants
pubmed: 31892516
pii: S0021-9258(17)48285-8
doi: 10.1074/jbc.RA119.011461
pmc: PMC7039573
pii:
doi:
Substances chimiques
Mutant Proteins
0
Peptides
0
Receptors, Thrombin
0
beta-Arrestins
0
Thrombin
EC 3.4.21.5
GTP-Binding Protein alpha Subunits, Gq-G11
EC 3.6.5.1
protease-activated receptor 4
JWE1M73YZN
Alanine
OF5P57N2ZX
Calcium
SY7Q814VUP
Banques de données
PDB
['5NDD']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2520-2540Subventions
Organisme : CIHR
ID : 376560
Pays : Canada
Informations de copyright
© 2020 Thibeault et al.
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