A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis

Araç, Demet; Boucard, Antony A.; Bolliger, Marc; Nguyen, Jennifer; Soltis, S. Michael; Südhof, Thomas C.; Brunger, Axel T.

doi:10.1038/emboj.2012.26

Cited by 382 publications

(612 citation statements)

References 62 publications

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“…However, because β-strand-13 is an essential structural component of GAIN domains, a functional ECD could not be purified without this element (Fig. S4A) (8). Therefore, we do not have absolute confirmation that a dissociated ECD could reinhibit the 7TM domain, although the possibility seems highly unlikely given structural and energetic considerations.…”

Section: Discussionmentioning

confidence: 67%

“…aGPCR GAIN domains are comprised predominantly of tightly packed β-strands and are sufficient to mediate autoproteolysis at the consensus site, HL/T ( Fig. 1) (8,14). β-strand-13 is buried deeply within the GAIN hydrophobic core and is an essential contributor to overall domain structural integrity despite being present C-terminal to the GAIN domain self-cleavage site.…”

Section: Resultsmentioning

confidence: 99%

“…aGPCRs are misregulated in developmental disorders and many cancers, and some aGPCRs are considered bona fide oncogenes (4)(5)(6)(7). This 33-member subclass of family B GPCRs is distinguished by large extracellular N termini that harbor various adhesion modules and a ∼320-aa GPCR autoproteolysis-inducing (GAIN) domain located proximal to the seven-transmembrane spanning domain (7TM) (8,9). GAIN-mediated receptor selfcleavage occurs constitutively during biosynthesis to produce receptors that have two protomers consisting of the extracellular domains (ECD) or N-terminal fragments (NTF) noncovalently bound to the 7TM or C-terminal fragments (CTF).…”

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confidence: 99%

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Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Stoveken¹,

Hajduczok²,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

227

385

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The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Stoveken¹,

Hajduczok²,

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

227

385

View full text Add to dashboard Cite

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“…It is required for cleavage of aGPCR pro-receptor molecules and mediates noncovalent reassociation of the cleaved fragments (Arac et al, 2012). However, GPS cleavage is dispensable for aGPCR function and the consensus GPS sequence is frequently lost in individual aGPCR homologs (Pr€ omel et al, 2012).…”

Section: Gpr111 and Gpr115 Are Not Autoproteolyzed At The Gps Motifmentioning

confidence: 99%

“…The defining structural feature of all aGPCR is the GPCR proteolytic site (GPS) motif (Krasnoperov et al, 1997), a juxtamembrane sequence embedded within a larger GPCR-autoproteolysis-inducing (GAIN) domain (Arac et al, 2012), which promotes proteolytic cleavage of an aGPCR pro-receptor into a two-subunit heteromeric complex (Lin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

Prömel

Waller-Evans

Dixon

et al. 2012

Developmental Dynamics

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Background: Adhesion G protein-coupled receptors (aGPCR) constitute a structurally and functionally diverse class of seven-transmembrane receptor proteins. Although for some of the members important roles in immunology, neurology, as well as developmental biology have been suggested, most receptors have been poorly characterized. Results: We have studied evolution, expression, and function of an entire receptor group containing four uncharacterized aGPCR: Gpr110, Gpr111, Gpr115, and Gpr116. We show that the genomic loci of these four receptors are clustered tightly together in mouse and human genomes and that this cluster likely derives from a single common ancestor gene. Using transcriptional profiling on wild-type and knockout/LacZ reporter knockin mice strains, we have obtained detailed expression maps that show ubiquitous expression of Gpr116, co-expression of Gpr111 and Gpr115 in developing skin, and expression of Gpr110 in adult kidney. Loss of Gpr110, Gpr111, or Gpr115 function did not result in detectable defects, indicating that genes of this aGPCR group might function redundantly. Conclusions: The aGPCR cluster Gpr110, Gpr111, Gpr115, and Gpr116 developed from one common ancestor in vertebrates. Expression suggests a role in epithelia, and one can speculate about a possible redundant function of GPR111 and GPR115. Developmental Dynamics 241:1591-1602, 2012.V C 2012 Wiley Periodicals, Inc.

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CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency

Vilboux

Malicdan

Roney

et al. 2017

American J of Med Genetics Pt A

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Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic "molar tooth sign" on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. © 2017 Wiley Periodicals, Inc.

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A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis

Cited by 382 publications

References 62 publications

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency

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