Conformational transitions and activation of the adhesion receptor CD97

Mao, Chunyou; Zhao, Ru-Jia; Dong, Ying-Jun; Gao, Mingxin; Chen, Li-Nan; Zhang, Chao; Xiao, Peng; Guo, Jia; Qin, Jiao; Shen, Dan-Dan; Ji, Su-Yu; Zang, Shao-Kun; Zhang, Huibing; Wang, Wei-Wei; Shen, Qingya; Sun, Jin-Peng; Zhang, Yan

doi:10.1016/j.molcel.2023.12.020

Cited by 4 publications

(4 citation statements)

References 84 publications

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“…5) close to the GPS may now be tested in any model system based on their GRN index. Analogously, we can now assess the location of known pathological mutations: Avila-Zozaya et al have investigated cancer-related mutations in ADGRL3, with impacts on G 13 -signaling for K561N H1.51 , D798H S9.47 , S810L s9s10 and E811Q s9s10 , where the latter two residues correspond to the interaction region of the GAIN domain with the seventransmembrane domain 19,53 . Two mutations responsible for loss of surface expression in GPR56, causing bilateral frontoparietal polymicrogyria (BFPP), are the highly conserved C346S S10.47 and W349S S10.50 ref 6,72,73 .…”

Section: Discussionmentioning

confidence: 99%

“…1), with mutations known to affect GAIN domain autoproteolysis and TA function: the conserved leucine at the S14.50 position (Supplementary Fig. 1) is a TA residue deeply buried into the orthosteric binding site of the 7TM domain in active aGPCR-7TM structures 19,[30][31][32][33][34]55 , and its mutation led to altered receptor activity 10,22,56,57 . Strikingly, the mutation of any tryptophane within the "VWWL" motif causes loss-offunction in rat ADGRL1 8 .…”

Section: A Map Of Cancer-enriched Mutations In the Gain Domainmentioning

confidence: 99%

“…1b), which corresponds to the N-terminus of the CTF that arises through GAIN domain cleavage [10][11][12][13] . The TA activates the receptor upon dissociation of the NTF/CTF complex 10,14-17 , the biophysical intricacies of which are yet to be uncovered 18,19 . Third, several aGPCRs act as metabotropic mechanosensors [20][21][22][23][24] , where the GAIN domain is proposed to serve as a molecular integrator of mechanical forces through its partial unfolding or eventual dissociation of the NTF/CTF complex upon force stimulation [25][26][27][28][29] .…”

Section: Introductionmentioning

confidence: 99%

“…The available set of GAIN domain structures indicates a common architecture with two, structurally variable subdomains: The more variable subdomain A is comprised of up to six helices, and the more conserved subdomain B adopts a β-sandwich with the TA as its most C-terminal strand (Fig. 1b-c) 8,9,19,[35][36][37] . The low sequence identity of GAIN domains and variable number of constituting segments, however, led to inadequate annotations of the GAIN domain in protein databases, hampering inter-species comparison of GAIN domains and limiting a holistic understanding of GAIN domain function.…”

Section: Introductionmentioning

confidence: 99%

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Generic residue numbering of the GAIN domain of adhesion GPCRs

Seufert,

Pérez-Hernández,

Pándy-Szekeres

et al. 2024

Preprint

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The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a concealed tethered agonist element, which is necessary and sufficient for receptor activation. The GAIN domain is a hotspot for pathological mutations. However, the low primary sequence conservation of GAIN domains has thus far hindered the knowledge transfer across different GAIN domains in human receptors as well as species orthologs. Here, we present a scheme for generic residue numbering of GAIN domains based on structural alignments of six experimental and more than 14,000 modeled GAIN domain structures. This scheme is implemented in the GPCR database (GPCRdb) and elucidates the domain topology across different aGPCRs and their homologs in a large panel of species. We identify conservation hotspots and cancer-enriched positions in human aGPCRs and show the transferability of positional and structural information between GAIN domain homologs. The GAIN-GRN scheme provides a robust strategy to allocate structural homologies at the primary and secondary levels also to GAIN folds of GAIN domains of polycystic kidney disease 1/PKD1-like proteins, which now renders positions in both GAIN domain types comparable to one another.

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Section: Discussionmentioning

confidence: 99%

Section: A Map Of Cancer-enriched Mutations In the Gain Domainmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Generic residue numbering of the GAIN domain of adhesion GPCRs

Seufert,

Pérez-Hernández,

Pándy-Szekeres

et al. 2024

Preprint

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Mechanical force induced activation of adhesion G protein–coupled receptor

Xu,

Yan

et al. 2024

Mechanobiology in Medicine

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The force-sensing GPCR LPHN2 is indispensable for normal auditory function

Yang,

Wang,

Zhou

et al. 2023

Preprint

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Auditory perception enables acoustic experiences, including listening to melodious music and engaging in linguistic communication. Conversion of the force sensation into electrical signals via mechanoelectrical transduction (MET) in cochlear hair cells is the key step for auditory perception; however, the sound receptor for auditory perception at the molecular level is not clear. Here, we found that hair cell-specific deficiency of the G protein-coupled receptor LPHN2 in Pou4f3-CreER+/-Lphn2fl/fl mice or pharmacological blockade of CNG ion channels in mice severely impaired hearing. Importantly, sensation of force by LPHN2 not only increased intracellular cAMP and calcium levels but also elicited rapid membrane depolarization of cochlear hair cells via Gs-dependent CNGA3 coupling. Both LPHN2 and CNGA3 were expressed at the stereocilia and cuticular plates and associated with each other. Notably, hearing loss in LPHN2-deficient mice was almost fully reversed by re-expression of LPHN2-GAIN in cochlear hair cells. Therefore, we propose that LPHN2 acts as a direct sound sensor in cochlear hair cells by mediating MET through Gs and CNGA3 coupling. Furthermore, both GPCR members and ion channels modulated by second messengers might actively participate in the MET process during auditory perception.

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Conformational transitions and activation of the adhesion receptor CD97

Cited by 4 publications

References 84 publications

Generic residue numbering of the GAIN domain of adhesion GPCRs

Generic residue numbering of the GAIN domain of adhesion GPCRs

Mechanical force induced activation of adhesion G protein–coupled receptor

The force-sensing GPCR LPHN2 is indispensable for normal auditory function

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