GRK5 antibody Polyclonal Antibodies Primary antibodies
- Known as:
- GRK5 (anti-) Polyclonal Antibodies Primary antibodies
- Catalog number:
- orb100004
- Product Quantity:
- 100
- Category:
- -
- Supplier:
- Biorb
- Gene target:
- GRK5 antibody Polyclonal Antibodies Primary antibodies
Related genes to: GRK5 antibody Polyclonal Antibodies Primary antibodies
- Gene:
- GRK5 NIH gene
- Name:
- G protein-coupled receptor kinase 5
- Previous symbol:
- GPRK5
- Synonyms:
- -
- Chromosome:
- 10q26.11
- Locus Type:
- gene with protein product
- Date approved:
- 1994-03-29
- Date modifiied:
- 2015-08-28
Related products to: GRK5 antibody Polyclonal Antibodies Primary antibodies
Related articles to: GRK5 antibody Polyclonal Antibodies Primary antibodies
- - Source: PubMed
Nieman Marvin T - G protein-coupled receptors (GPCRs) are the largest class of membrane proteins and the most common pharmaceutical drug target. Prior work from our group and others supports that a conserved, proline-hydrophobic residue (ProH) motif within intracellular loop-2 (ICL2) biases GPCR-transducer coupling between canonical G proteins and β-arrestin (βarr). Here, we systematically characterize a rare missense mutation within the ProH motif of the ghrelin receptor (growth hormone secretagogue receptor [GHSR])-Leu149Pro (L149P)-to dissect how naturalistic perturbation of ICL2 dynamics pleiotropically regulates the spatial distribution, trafficking, and transducer selectivity of a prototypical, rhodopsin-like GPCR. Molecular dynamics simulations indicate that the L149P mutation destabilizes the α-helical conformation of ICL2, thereby increasing loop flexibility proximal to the receptor-transducer coupling interface. Using a panel of bioluminescence resonance-energy transfer biosensors combined with pharmacological and genetic tools, we demonstrate that the GHSR-L149P mutation (1) enhances receptor surface expression by reducing constitutive GHSR trafficking; (2) biases transducer engagement toward βarr1/2 and Gα over Gα and Gα, despite partial mini-G coupling efficacy; (3) expands GPCR kinase (GRK) subclass utilization from GRK2/3-dependent to an additional, partial reliance on GRK5/6; and (4) promotes βarr1/2 recruitment independent of G protein-mediated second messenger kinase activation. The evolutionary conservation of the ProH motif suggests that cognate, ICL2-destabilizing variants likely confer comparable disruptions in GPCR structure/function beyond established effects on G protein coupling. Collectively, these results establish a naturalistic model to study ICL2-dependent GPCR regulation and illuminate the ProH motif as a promising drug target for biased allosteric modulators. SIGNIFICANCE STATEMENT: G protein-coupled receptors are the most common pharmaceutical target in medicine. This study exploited a rare variant in intracellular loop-2 of the ghrelin receptor to characterize a conserved, allosteric "hotspot" controlling G protein-coupled receptor expression, trafficking, and signaling. These findings highlight intracellular loop-2 as a promising target for biased allosteric modulator drug design. - Source: PubMed
Publication date: 2026/03/13
Balfe Elsa MTorbey AlexandreStepniewski Tomasz MZhou YangKohlenbach LaraSency Jade AInoue AsukaSlosky Lauren MSelent JanaBarak Lawrence SGross Joshua D - G protein-coupled receptor kinase 5 (GRK5) is an important therapeutic target involving cardiovascular diseases, cancer, and inflammatory disorders. However, the features of its activation as an essential function regulation process have been poorly understood, limiting related drug development. The work utilizes a molecular dynamics simulation coupled with an interpretable machine learning model to identify key structure and dynamics determinants distinguishing the active and inactive states of GRK5. Benefiting from the unbiased and data-driven framework, the work reveals that the active site tether (AST) is a dominant activation-associated feature, acting as a conformational switch that regulates kinase domain movements. Beyond this canonical element, we also uncover two previously underappreciated structure modules contributing to GRK5 activation, such as the coupling interaction between the α10/α11 helix interface with the N-terminal lipid-binding domain (NLBD) in the active state, and the α5 helix region that facilitates large-scale RH domain reorientation. Conformation dynamics analyses further indicate that GRK5 activation involves disruption of the interdomain interactions and interaction coupling between AST, αN-helix, kinase domain N-lobe, NLBD, and α10/α11 hinge. These observations provide valuable insights into understanding the GPK5 activation mechanism and also highlight the power of machine learning in capturing functionally conformational changes, and in turn offering a methodological guideline for the studying of the protein function mechanism. - Source: PubMed
Publication date: 2026/04/07
Song YuanpengKong MingZhang FuhuiPu Xuemei - G protein-coupled receptors (GPCRs) exhibit signaling bias or preferential activation of heterotrimeric G proteins versus GPCR kinase (GRK)-mediated β-arrestin signaling. The protease-activated receptor-1 (PAR1) activates both G protein and β-arrestin in response to thrombin but only β-arrestin in response to activated protein C (APC). Thrombin-activated PAR1-G protein signaling is desensitized by β-arrestin-1, whereas APC-activated PAR1 signaling is propagated by β-arrestin-2. The mechanisms underlying PAR1 biased signaling are not known. Here, using computational modeling combined with cellular and biochemical studies, we reveal the molecular basis of signaling by thrombin- and APC-activated PAR1. Although both thrombin- and APC-induced PAR1 signaling are regulated by the same GRK, GRK5, the two types of signaling are differentially dependent on GRK5 membrane anchoring, PAR1 C-terminal phosphorylation sites, and the binding mode of β-arrestin-2. These differences translate into distinct β-arrestin-2 conformations and define the APC cytoprotective signaling signature, which contrasts with thrombin inflammatory signaling. - Source: PubMed
Publication date: 2026/03/03
Gonzalez Ramirez Monica LOrduña-Castillo Lennis BBardeleben CarolyneQin HuapingLin YingBirch Cierra AKufareva IrinaTrejo JoAnn - G-protein-coupled receptors (GPCRs) display bias toward either G proteins or GPCR kinase (GRK)-mediated β-arrestin (βarr) signaling depending on the agonist-stabilized receptor conformation. The cellular context and subcellular location of GPCRs can also influence biased signaling through mechanisms that are not well understood. The protease-activated receptor-1 (PAR1) exhibits signaling bias in response to thrombin and activated protein C (APC). APC-induced βarr2-biased signaling requires PAR1 compartmentalization in caveolae, a subtype of lipid rafts, whereas thrombin-activated PAR1 G protein signaling does not. Caveolin-1 (Cav1) is the principal structural component of caveolae and regulates protein-protein interactions. The mechanisms by which Cav1 contributes to APC-PAR1-induced βarr2-biased signaling are not known. Here, we report that a substantial population of endogenous PAR1 colocalizes with Cav1 in endothelial cells and is modulated by APC, assessed by single-molecule super-resolution stochastic optical reconstruction microscopy imaging. APC activation of PAR1 also induces Cav1 tyrosine-14 phosphorylation through a βarr2- and c-Src-dependent pathway, which disrupts PAR1-Cav1 coassociation. A smaller population of endogenous GRK5 was also found to colocalize with Cav1 in endothelial cells and was modestly altered by APC activation of PAR1. Moreover, GRK5 was found to interact with Cav1 in intact cells through an N-terminal aromatic-rich Cav1 binding motif. Mutation of this motif disrupts GRK5-Cav1 binding, shifts GRK5 predominantly to the cytoplasm rather than the plasma membrane, and perturbs GRK5-mediated βarr2 recruitment to APC-activated PAR1. Thus, beyond its structural function, Cav1 participates in protein-protein interactions with PAR1 and GRK5, two key effectors that enable APC-induced βarr2 signaling. - Source: PubMed
Publication date: 2026/01/23
Qin HuapingOrduña-Castillo Lennis BMolinar-Inglis OliviaGonzalez Ramirez Monica LLopez-Ramirez Miguel ABardeleben CarolyneTrejo JoAnn