Ageing Research Reviews, Год журнала: 2024, Номер 99, С. 102377 - 102377
Опубликована: Июнь 12, 2024
Язык: Английский
Cell, Год журнала: 2020, Номер 181(3), С. 536 - 556
Опубликована: Апрель 1, 2020
Язык: Английский
Процитировано
298
The Journal of Cell Biology, Год журнала: 2021, Номер 220(7)
Опубликована: Июнь 4, 2021
In a neural circuit, synapses transfer information rapidly between neurons and transform this during transfer. The diverse computational properties of are shaped by the interactions pre- postsynaptic neurons. How assembled to form how specificity synaptic connections is achieved, largely unknown. Here, I posit that adhesion molecules (SAMs) organize synapse formation. Diverse SAMs collaborate achieve astounding plasticity synapses, with each SAM contributing different facets. orchestrating assembly, likely act as signal transduction devices. Although many candidate known, only few appear have major impact on Thus, limited set collaborating suffices account for Strikingly, several genetically linked neuropsychiatric disorders, suggesting impairments in assembly instrumental pathogenesis disorders.
Язык: Английский
Процитировано
252
Nature, Год журнала: 2021, Номер 589(7843), С. 620 - 626
Опубликована: Янв. 6, 2021
Язык: Английский
Процитировано
135
Nature, Год журнала: 2022, Номер 604(7907), С. 757 - 762
Опубликована: Апрель 13, 2022
Язык: Английский
Процитировано
103
Nature, Год журнала: 2022, Номер 604(7907), С. 779 - 785
Опубликована: Апрель 13, 2022
Abstract Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis 1–7 . An intrinsic manner activation that involves tethered agonist in the N-terminal region receptor has been proposed aGPCRs 8,9 , but its molecular mechanism remains elusive. Here we report protein-bound structures ADGRD1 ADGRF1, which exhibit many unique features with regard to agonism. The stalk proceeds first transmembrane helix acts by forming extensive interactions domain; these mostly conserved suggesting common stalk–transmembrane domain interaction pattern is shared members aGPCR family. A similar binding mode observed structure autoproteolysis-deficient supporting cleavage-independent activation. stalk-induced facilitated cascade inter-helix cores positions show sequence variability two aGPCRs. Furthermore, intracellular ADGRF1 contains specific lipid-binding site, proves be functionally important may serve recognition site previously discovered endogenous ligand synaptamide. These findings highlight diversity complexity signal transduction mechanisms
Язык: Английский
Процитировано
87
Nature, Год журнала: 2024, Номер 626(7997), С. 128 - 135
Опубликована: Янв. 17, 2024
Abstract The assembly and specification of synapses in the brain is incompletely understood 1–3 . Latrophilin-3 (encoded by Adgrl3 , also known as Lphn3 )—a postsynaptic adhesion G-protein-coupled receptor—mediates synapse formation hippocampus 4 but mechanisms involved remain unclear. Here we show mice that LPHN3 organizes through a convergent dual-pathway mechanism: activation Gα s signalling recruitment phase-separated protein scaffolds. We found cell-type-specific alternative splicing controls G-protein-coupling mode, resulting variants predominantly signal or 12/13 CRISPR-mediated manipulation shifts from - to -coupled mode impaired synaptic connectivity severely overall deletion suggesting splice mediates formation. Notably, -coupled, not recruit phase-transitioned scaffold condensates, such these condensates are clustered binding presynaptic teneurin FLRT ligands LPHN3. Moreover, neuronal activity promotes synaptogenic variant Together, data suggest activity-dependent key molecule parallel two pathways: phase separation
Язык: Английский
Процитировано
33
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Март 8, 2024
Abstract Neuronal mitochondria play important roles beyond ATP generation, including Ca 2+ uptake, and therefore have instructive in synaptic function neuronal response properties. Mitochondrial morphology differs significantly between the axon dendrites of a given subtype, but CA1 pyramidal neurons (PNs) hippocampus, within dendritic arbor also display remarkable degree subcellular, layer-specific compartmentalization. In these neurons, ranges from highly fused elongated apical tuft, to more fragmented oblique basal compartments, thus occupy smaller fraction volume than tuft. However, molecular mechanisms underlying this striking subcellular compartmentalization are unknown, precluding assessment its impact on function. Here, we demonstrate that compartment-specific requires activity-dependent, Camkk2-dependent activation AMPK ability phosphorylate two direct effectors: pro-fission Drp1 receptor Mff recently identified anti-fusion, Opa1-inhibiting protein, Mtfr1l. Our study uncovers signaling pathway mitochondrial vivo through spatially precise activity-dependent regulation fission/fusion balance.
Язык: Английский
Процитировано
20
Cell Research, Год журнала: 2025, Номер unknown
Опубликована: Фев. 18, 2025
Abstract Equilibrioception (sensing of balance) is essential for mammals to perceive and navigate the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells crucial detecting position motion. Here, we identify G protein-coupled receptor (GPCR) LPHN2/ADGRL2, expressed on apical membrane utricular cells, as maintaining normal balance. Loss LPHN2 specifically impaired both balance behavior MET mice. Functional analyses using hair-cell-specific Lphn2 -knockout mice an LPHN2-specific inhibitor suggest that regulates tip-link-independent currents at surface cells. Mechanistic studies a heterologous system show converts force stimuli into increased open probability transmembrane channel-like protein 1 (TMC1). LPHN2-mediated sensation triggers glutamate release calcium signaling Importantly, reintroducing -deficient restores function response. Our data reveal mechanosensitive GPCR required equilibrioception.
Язык: Английский
Процитировано
4
Journal of Biological Chemistry, Год журнала: 2020, Номер 295(41), С. 14065 - 14083
Опубликована: Авг. 6, 2020
Adhesion G protein–coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control wide array physiological processes and implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions range from hundreds to thousands residues length. AGPCR autoproteolysis occurs within the GPCR autoproteolysis-inducing (GAIN) domain is proximal N terminus protein–coupling seven-transmembrane–spanning bundle. GAIN domain–mediated self-cleavage constitutive produces two-fragment holoreceptors remain bound at cell surface. It has been recent interest understand how activated relation their topologies. Dissociation fragments stimulates protein signaling through action tethered-peptide agonist stalk occluded holoreceptor form. can also signal independently fragment dissociation, few possess domains incapable self-proteolysis. This resulted complex theories as these vivo, complicating pharmacological advances. Currently, there no existing structure an support any theories. Further confounding research many orphans lack identified activating ligands. In this review, we provide detailed layout current theorized modes activation with discussion potential parallels mechanisms used by other classes. We classification means for ligands have discuss may activate contexts. (GPCRs) largest class membrane receptors, comprising over 800 members humans. The seven-transmembrane helical bundle (7TM) allows regulation distinct cascades response diverse stimuli. Due broad influence on health disease, heavily investigated intervention targets approved drugs (1Rask-Andersen M. Masuram S. Schiöth H.B. druggable genome: evaluation drug clinical trials suggests major shifts molecular indication.Annu. Rev. Pharmacol. Toxicol. 2014; 54 (24016212): 9-2610.1146/annurev-pharmtox-011613-135943Crossref PubMed Scopus (161) Google Scholar). Consequently, study each individual subclass will unique angles beneficial development therapeutics. Canonically, initiated binding its orthosteric site, which results rearrangements transmembrane helices 7TM allow efficient heterotrimeric coupling activation. α subunits exchange GDP GTP, allowing functional dissociation Gβγ downstream effectors. divided into six classes follows in-class examples: A (rhodopsin-like), (secretin), C (metabotropic glutamate), D (pheromone), E (cAMP), F (Frizzled) (2Attwood T.K. Findlay J.B. Fingerprinting G-protein-coupled receptors.Protein Eng. 1994; 7 (8170923): 195-20310.1093/protein/7.2.195Crossref Scholar, 3Krishnan A. Almén M.S. Fredriksson R. origin GPCRs: identification mammalian like rhodopsin, adhesion, glutamate frizzled fungi.PLoS ONE. 2012; (22238661): e2981710.1371/journal.pone.0029817Crossref (105) 4Fredriksson Lagerström M.C. Lundin L.G. human genome form five main families: phylogenetic analysis, paralogon groups, fingerprints.Mol. 2003; 63 (12761335): 1256-127210.1124/mol.63.6.1256Crossref (1871) Within naming system, adhesion family but more aptly termed B2, whereas traditional peptide hormone-binding comprise B1. distinguished not only large (ECRs) variety adhesive subdomains, highly conserved autoproteolysis–inducing constitutively self-cleaves two (5Araç D. Boucard A.A. Bolliger M.F. Nguyen J. Soltis S.M. Südhof T.C. Brunger A.T. novel evolutionarily cell-adhesion mediates autoproteolysis.EMBO 31 (22333914): 1364-137810.1038/emboj.2012.26Crossref (204) Whereas extensive work done characterize AGPCRs, it largely uncertain they endogenous tissues. How ligand-ECR regulates state arguably most intensely studied problem research. To date, involving allosteric modulation proposed. Here, sought clarity detailing structural topologies while examining prospective actions models be compared established Select aspects discussed routes receptor outlined review consistent framework develop thought mechanistic considerations advance structures await solution. As knowledge function increases, realization untapped therapeutic increase, prompting efforts target them. 33 (ADGRs) among nine subfamilies, ADGRA–G, -L, -V, based sequence similarity (6Bjarnadóttir Höglund P.J. Gloriam D.E. mouse repertoire receptors.Genomics. 2004; 84 (15203201): 23-3310.1016/j.ygeno.2003.12.004Crossref (0) 7Hamann Aust G. Araç Engel F.B. Formstone C. Hall R.A. Harty B.L. Kirchhoff Knapp B. Krishnan Liebscher I. Lin H.-H. Martinelli D.C. Monk K.R. et al.International union basic pharmacology. XCIV. receptors.Pharmacol. 2015; 67 (25713288): 338-36710.1124/pr.114.009647Crossref known proteins cases. N-terminal ECRs often share common characteristics same subfamily. related subdomains repeated (Fig. 1A, multicolored nodules). For example, group include ADGRE (EMR (EGF-like module–containing mucin-like hormone receptor)) epidermal growth factor–like repeats found types mediate cell-adhesive interactions (8McKnight A.J. Gordon EGF-TM7: seven-transmembrane-region leukocyte cell-surface molecules.Immunol. Today. 1996; 17 (8962632): 283-28710.1016/0167-5699(96)80546-9Abstract Full Text PDF 9Lin Stacey Hamann McKnight Human EMR2, EGF-TM7 molecule chromosome 19p13.1, closely CD97.Genomics. 2000; (10903844): 188-20010.1006/geno.2000.6238Crossref Twelve ∼70-residue (HormR) located N-terminally domain. There yet report binds AGPCR, leading believe HormR additional functions beyond 1E) (10Arac Strater N. Seiradake E. Understanding basis functions.Handb. Exp. 2016; 234 (27832484): 67-8210.1007/978-3-319-41523-9_4Crossref (17) Another interesting motif select sperm protein, enterokinase, agrin (SEA) ADGRF1 (GPR110), ADGRF5 (GPR116), ADGRG6 (GPR126) (11Lum A.M. Wang B.B. Beck-Engeser G.B. Li L. Channa Wabl Orphan GPR110, oncogene overexpressed lung prostate cancer.BMC Cancer. 2010; 10 (20149256): 4010.1186/1471-2407-10-40Crossref (33) 12Abe Fukuzawa T. Hirose Cleavage Ig-Hepta "SEA" module protein-coupled proteolytic site.J. Biol. Chem. 2002; 277 (11973329): 23391-2339810.1074/jbc.M110877200Abstract (61) 13Leon K. Cunningham R.L. Riback J.A. Feldman Sosnick T.R. Zhao Structural Gpr126 function.Nat. Commun. 2020; 11 (31924782): 19410.1038/s41467-019-14040-1Crossref (8) SEA second autoproteolytic cleavage event self-cleavage. Not much about role domain, leaves open possibility particular alternative regulation. At C-terminal end nearly every ECR, ending 7–18 prior start first span bundle, Scholar) 1A). seminal finding field was X-ray crystallographic solution subdomains: α-helix–rich GAINA β-sandwich GAINB. Complete ∼320 amino acids variability typically observed subdomain. indicated name, fully self-sufficient protease catalyzes splits fragments. Autoproteolytic believed cases, some studies raised might regulated, although consideration overexpression artifacts merited 14Hsiao C.C. Cheng K.F. Chen H.Y. Chou Y.H. Chang G.W. H.H. Site-specific N-glycosylation GPS auto-proteolysis CD97.FEBS Lett. 2009; 583 (19737555): 3285-329010.1016/j.febslet.2009.09.001Crossref (26) 15Wei W. Hackmann Xu H. Germino Qian F. Characterization cis-autoproteolysis polycystin-1, product polycystic kidney disease 1 gene.J. 2007; 282 (17525154): 21729-2173710.1074/jbc.M703218200Abstract (74) remaining after (NTF) or ECR membrane-intercalated (CTF), referred dense network hydrogen bonds NTF CTF noncovalently self-proteolysis, considered occur early during biosynthesis intracellular compartment (16Nieberler Kittel R.J. Petrenko A.G. Langenhan Control processing.Handb. (27832485): 83-10910.1007/978-3-319-41523-9_5Crossref (20) trafficked plasma where resides, poised signaling. self-proteolysis reaction requires proper folding GAINB when residue P2 position site abstracts side chain conserved, polar threonine (or serine) P1′ 1B) (17Lin Davies J.Q. Harris Autocatalytic EMR2 motif.J. 279 (15150276): 31823-3183210.1074/jbc.M402974200Abstract (135) commonly histidines, such His-836 ADGRL1 (latrophilin (LPHN1)), arginine, Arg-855 ADGRB5 (BAI3) proton abstraction initiates nucleophilic attack carbonyl P1 residue, leucine. resulting ester intermediate resolved final water molecule. consensus HL/T. Prior structure, HL/T surrounding proteolysis (GPS), reflecting idea minimal sufficient rather than larger (18Krasnoperov V. Lu Y. Buryanovsky Neubert T.A. Ichtchenko Post-translational processing calcium-independent α-latrotoxin (CIRL), natural chimera receptor: (GPS) (12270923): 46518-4652610.1074/jbc.M206415200Abstract 19Prömel Matching function: adhesion-GPCR PKD1-like proteins.Trends Sci. 2013; 34 (23850273): 470-47810.1016/j.tips.2013.06.002Abstract (47) 20Krasnoperov Bittner M.A. Holz R.W. Chepurny O. requirements α-latrotoxin-stimulated secretion: (CIRL) deletion mutants.J. 1999; 274 (9920906): 3590-359610.1074/jbc.274.6.3590Abstract Given original definition changed, now come mean 14–25 (TM1). CTF, threonine, immediately (13th) β-strand comprises Therefore, 13 part embedded GAINB, (i.e. HL/T) essentially loop links β-strands 12 1C). β-Strand sequences very hydrophobic, aligns location interior core subdomain (C–E) Table 1). ∼20 hold firmly Scholar).Table 1Adhesion tethered agonist/β-Strand sequences* ADGRA1 (GPR123) does thus GPS. Open table new tab * years, connects TM1 includes named (also agonist). multiple shown groups play pivotal mediating (21Stoveken H.M. Hajduczok Tall G.G. exposure cryptic agonist.Proc. Natl. Acad. U. 112 (25918380): 6194-619910.1073/pnas.1421785112Crossref (102) 22Liebscher Schön Petersen S.C. Fischer Auerbach Demberg L.M. Mogha Cöster Simon K.-U. Rothemund Schöneberg ectodomain activates GPR126 GPR133.Cell Rep. 9 (25533341): 2018-202610.1016/j.celrep.2014.11.036Abstract (120) One feature seems obvious requirement agonism must become dissociated liberate Many currently deciphering exactly intersects varied mechanisms, below. Interestingly, all undergo autoproteolysis; including ADGRC1 (cadherin EGF LAG seven-pass G-type (CELSR1)), ADGRA2 (GPR124), ADGRF2 (GPR111), ADGRA3 (GPR125), ADGRF4 (GPR115), do involve (23Formstone C.J. Moxon Murdoch Little P. Mason Basal enrichment neuroepithelia function(s) Celsr1 protein.Mol. Cell Neurosci. 44 (20353824): 210-22210.1016/j.mcn.2010.03.008Crossref 24Vallon Essler Proteolytically processed soluble tumor endothelial marker (TEM) 5 survival angiogenesis linking integrin αvβ3 glycosaminoglycans.J. 2006; 281 (16982628): 34179-3418810.1074/jbc.M605291200Abstract 25Prömel Waller-Evans Dixon Zahn Colledge W.H. Doran Carlton M.B.L. Grosse Russ A.P. cluster four orphan mouse.Dev. Dyn. 241 (22837050): 1591-160210.1002/dvdy.23841Crossref (35) Impaired attributed alterations GPS; lacking (e.g. ADGRF4) position. ADGRC1) demonstrate (Table 1) Differences post-translational modifications proposed regulate GAIN-mediated cleavage, N-linked glycosylation events However, observations inefficient instances manifestations experimental impart improper trafficking processing. Noncleaved still capable signaling, leaving question activated. exhibit different basal activity levels depend receptor. one occupy dynamic energy landscape active inactive conformations (26Manglik Kobilka dynamics insights β2AR rhodopsin.Curr. Opin. 27 (24534489): 136-14310.1016/j.ceb.2014.01.008Crossref (154) 27Hilger Masureel B.K. Structure complexes.Nat. Struct. Mol. 2018; 25 (29323277): 4-1210.1038/s41594-017-0011-7Crossref (207) 28Xu Hu Kaindl Risel Hubner Maeda Niu X. Gmeiner Jin Conformational complexity muscarinic revealed NMR spectroscopy.Mol. Cell. 2019; 75 (31103421): 53-65.e5710.1016/j.molcel.2019.04.028Abstract (16) Fig. 2 depicts states cartoon diagrams representation protein–binding dynamism Accompanying profiles relative strength. An understanding ways emerging. imaginative schemes 29Purcell R.H. targets.Annu. 58 (28968187): 429-44910.1146/annurev-pharmtox-010617-052933Crossref 30Langenhan receptors—candidate metabotropic mechanosensors targets.Basic Clin. 126 (30859707): 5-1610.1111/bcpt.13223Crossref (6) 31Kishore Versatile GPCRs.Handb. (27832487): 127-14610.1007/978-3-319-41523-9_7Crossref (21) 32Paavola K.J. receptors: pharmacology, activation.Mol. 82 (22821233): 777-78310.1124/mol.112.080309Crossref (72) 33Folts Giera Piao neurological diseases.Trends 40 (30871735): 278-29310.1016/j.tips.2019.02.003Abstract (14) 34Liebscher Schoneberg Tethered agonism: mechanism (27832486): 111-12510.1007/978-3-319-41523-9_6Crossref (28) evidence supports fundamental modulation: agonism), NTF/CTF required, regulation, tunable model require subunit 35Langenhan Sticky signaling–adhesion take stage.Sci. Signal. 6 (23695165): re310.1126/scisignal.2003825Crossref (151) Both supported several lines evidence, likely both manners. Orthosteric depends agonist. important residues, agonist, seven These mostly overlap 13, conformation adopts TXFAVLM, T, F, M showing highest conversation across colleagues (36Paavola Stephenson J.R. Ritter S.L. Alter S.P. GPR56 controls activity.J. 2011; 286 (21708946): 28914-2892110.1074/jbc.M111.247973Abstract (101) provided isolated cognate holoreceptor. strengths ADGRG1 (GPR56) engineered construct entirety deleted (ΔNTF, CTF) were compared. ΔNTF exhibited substantially higher protein–dependent full-length Since then, variants increased capacity
Язык: Английский
Процитировано
138
Cell, Год журнала: 2020, Номер 180(2), С. 323 - 339.e19
Опубликована: Янв. 1, 2020
Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, FLRT proteins also expressed during murine cortical migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes reveal how lectin olfactomedin domains Latrophilin bind across spiraling beta-barrel domain Teneurin, YD shell. We couple structure-based protein engineering to biophysical analysis, assays, utero electroporation experiments probe importance interaction neuron migration. show binding Latrophilins FLRTs directs neurons using contact repulsion-dependent mechanism. effect is observed bodies small neurites rather than their processes. results exemplify structure-encoded used for repulsive guidance.
Язык: Английский
Процитировано
122