Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism

Abstract

TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca2+ permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols. Two distinct states of mTRPML1 in Amphipols are added to the closed state, on which could represent two different confirmations upon activation and regulation. The polycystin-mucolipin domain (PMD) may sense the luminal/extracellular stimuli and undergo a “move upward” motion during endocytosis, thus triggering the overall conformational change in TRPML1. Based on the structural comparisons, we propose TRPML1 is regulated by pH, Ca2+, and phosphoinositides in a combined manner so as to accommodate the dynamic endocytosis process.

Keywords

mTRPML1 / mucolipidosis type IV / structual comparisons / combined regulation mechanism

References

[1] AhujaM, ParkS, ShinDM, MuallemS (2016) TRPML1 as lysosomal fusion guard.Channels (Austin)10:261–263

[2] AppelqvistH, WasterP, KagedalK, OllingerK (2013) The lysosome: from waste bag to potential therapeutic target.J Mol Cell Biol5:214–226

[3] BachG (2005) Mucolipin 1: endocytosis and cation channel–a review.Pflugers Arch451:313–317

[4] BargalR, AvidanN, Ben-AsherE, OlenderZ, ZeiglerM, FrumkinA, Raas-RothschildA, GlusmanG, LancetD, BachG (2000) Identification of the gene causing mucolipidosis type IV.Nat Genet26:118–123

[5] BargalR, AvidanN, OlenderT, Ben AsherE, ZeiglerM, Raas-RothschildA, FrumkinA, Ben-YosephO, FriedlenderY, Lancet D (2001) Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population.Hum Mutat17:397–402

[6] BenemeiS, PatacchiniR, TrevisaniM, GeppettiP (2015) TRP channels.Curr Opin Pharmacol22:18–23

[7] BermanER, LivniN, ShapiraE, MerinS, LevijIS (1974) Congenital corneal clouding with abnormal systemic storage bodies: a new variant of mucolipidosis.J Pediatr84:519–526

[8] BundeySE, AshenhurstEM, DorstJP (1974) Mucolipidosis, probably a new variant with joint deformity and peripheral nerve dysfunction.Birth Defects Orig Artic Ser10:484–490

[9] CaoE, LiaoM, ChengY, JuliusD (2013) TRPV1 structures in distinct conformations reveal activation mechanisms.Nature504:113–118

[10] ChenS, McMullanG, FaruqiAR, MurshudovGN, ShortJM, ScheresSH, HendersonR (2013) High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy.Ultramicroscopy135:24–35

[11] ChenCC, KellerM, HessM, SchiffmannR, UrbanN, WolfgardtA, SchaeferM, BracherF, BielM,Wahl-SchottC (2014) A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV.Nat Commun5:4681

[12] ChengX, ShenD, SamieM, XuH (2010) Mucolipins: Intracellular TRPML1-3 channels.FEBS Lett584:2013–2021

[13] ChengX, ZhangX, YuL, XuH (2015) Calcium signaling in membrane repair.Semin Cell Dev Biol45:24–31

[14] CivjanNR, BayburtTH, SchulerMA, SligarSG (2003) Direct solubilization of heterologously expressed membrane proteins by incorporation into nanoscale lipid bilayers.BioTechniques35:556–560

[15] ClaphamDE (2003) TRP channels as cellular sensors.Nature426:517–524

[16] ClaphamDE, RunnelsLW, StrubingC (2001) The TRP ion channel family.Nat Rev Neurosci2:387–396

[17] CollettiGA, KiselyovK (2011) Trpml1.Adv Exp Med Biol704:209–219

[18] DongXP, ShenD, WangX, DawsonT, LiX, ZhangQ, ChengX, ZhangY, WeismanLS, DellingM (2010a) PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca (2+) release channels in the endolysosome.Nat Commun1:38

[19] DongXP, Wang X, XuHX (2010b) TRP channels of intracellular membranes.Journal of Neurochemistry113:313–328

[20] EmsleyP, LohkampB, Scott WG, CowtanK (2010) Features and development of Coot.Acta Crystallogr D Biol Crystallogr66:486–501

[21] EverettKV (2011) Transient receptor potential genes and human inherited disease.Adv Exp Med Biol704:1011–1032

[22] FlockerziV (2007) An introduction on TRP channels.Handb Exp Pharmacol179:1–19

[23] GaoY, CaoE, JuliusD, ChengY (2016) TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.Nature534:347–351

[24] GeesM, OwsianikG, NiliusB, VoetsT (2012) TRP channels.Compr Physiol2:563–608

[25] GriebenM, PikeAC, ShintreCA, VenturiE, El-AjouzS, TessitoreA, ShresthaL, MukhopadhyayS, MahajanP, ChalkR (2017) Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2).Nat Struct Mol Biol24:114–122

[26] HanCY, WangXL (2008) Recent advances on TRP channels.Sheng Li Ke Xue Jin Zhan39:27–32

[27] HofherrA, WagnerC, FedelesS, SomloS, KottgenM (2014) N-glycosylation determines the abundance of the transient receptor potential channel TRPP2.J Biol Chem289:14854–14867

[28] HuynhKW, CohenMR, JiangJ, SamantaA, LodowskiDT, ZhouZH, Moiseenkova-BellVY (2016) Structure of the full-length TRPV2 channel by cryo-EM.Nat Commun7:11130

[29] JinP, BulkleyD, GuoY, ZhangW, GuoZ, HuynhW, WuS, MeltzerS, ChengT, JanLY (2017) Electron cryo-microscopy structure of the mechanotransduction channel NOMPC.Nature547:118–122

[30] KimaniusD, ForsbergBO, ScheresSH, LindahlE (2016) Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2.Elife. doi:10.7554/eLife.18722

[31] KiselyovK, ChenJ, RbaibiY, OberdickD, Tjon-Kon-SangS, ShcheynikovN, MuallemS, SoyomboA (2005) TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage.The Journal of biological chemistry280:43218–43223

[32] KucukelbirA, SigworthFJ, TagareHD (2014) Quantifying the local resolution of cryo-EM density maps.Nat Methods11:63–65

[33] LiX, MooneyP, ZhengS, BoothCR, BraunfeldMB, GubbensS, AgardDA, ChengY (2013) Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM.Nat Methods10:584–590

[34] LiX, ZhengS, AgardDA, ChengY (2015) Asynchronous data acquisition and on-the-fly analysis of dose fractionated cryoEM images by UCSFImage.J Struct Biol192:174–178

[35] LiM, ZhangWK, BenvinNM, ZhouX, SuD, LiH, WangS, MichailidisIE, TongL, LiX (2017) Structural basis of dual Ca2+/pH regulation of the endolysosomal TRPML1 channel.Nat Struct Mol Biol24:205–213

[36] LongSB, CampbellEB, MackinnonR (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel.Science309:897–903

[37] MinkeB (2006) TRP channels and Ca²⁺ signaling.Cell Calcium40:261–275

[38] PaulsenCE, ArmacheJP, GaoY, ChengY, JuliusD (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms.Nature525:552

[39] PedersenSF, OwsianikG, NiliusB (2005) TRP channels: an overview.Cell Calcium38:233–252

[40] PettersenEF, GoddardTD, HuangCC, CouchGS, GreenblattDM, MengEC, FerrinTE (2004) UCSF Chimera–a visualization system for exploratory research and analysis.J Comput Chem25:1605–1612

[41] PuertollanoR, KiselyovK (2009) TRPMLs: in sickness and in health.Am J Physiol Renal Physiol296:F1245–F1254

[42] QianF, Noben-TrauthK (2005) Cellular and molecular function of mucolipins (TRPML) and polycystin 2 (TRPP2).Pflugers Arch451:277–285

[43] RamseyIS, DellingM, ClaphamDE (2006) An introduction to TRP channels.Annu Rev Physiol68:619–647

[44] RitchieTK, GrinkovaYV, BayburtTH, DenisovIG, ZolnerciksJK, AtkinsWM, SligarSG (2009) Chapter 11—reconstitution of membrane proteins in phospholipid bilayer nanodiscs.Methods Enzymol464:211–231

[45] RohouA, GrigorieffN (2015) CTFFIND4: Fast and accurate defocus estimation from electron micrographs.J Struct Biol192:216–221

[46] SamieM, WangX, ZhangX, GoschkaA, LiX, ChengX, GreggE, AzarM, ZhuoY, GarrityAG (2013) A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis.Dev Cell26:511–524

[47] ScheresSH (2012) RELION: implementation of a Bayesian approach to cryo-EM structure determination.J Struct Biol180:519–530

[48] ScheresSH, ChenS (2012) Prevention of overfitting in cryo-EM structure determination.Nat Methods9:853–854

[49] ShaikhTR, GaoH, BaxterWT, AsturiasFJ, BoissetN, LeithA, FrankJ (2008) SPIDER image processing for single-particle reconstruction of biological macromolecules from electron micrographs.Nat Protoc3:1941–1974

[50] ShenPS, YangX, DeCaenPG, LiuX, BulkleyD, ClaphamDE, CaoE (2016) The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs.Cell167(763–773):e711

[51] SmartOS, NeduvelilJG, WangX, WallaceBA, SansomMS (1996) HOLE: a program for the analysis of the pore dimensions of ion channel structural models.J Mol Graph14(354–360):376

[52] SunM, GoldinE, StahlS, FalardeauJL, KennedyJC, AciernoJS Jr, BoveC, KaneskiCR, NagleJ, BromleyMC (2000) Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel.Hum Mol Genet9:2471–2478

[53] VenkatachalamK, MontellC (2007) TRP channels.Annu Rev Biochem76:387–417

[54] VenkatachalamK, WongCO, ZhuMX (2015) The role of TRPMLs in endolysosomal trafficking and function.Cell Calcium58:48–56

[55] VergarajaureguiS, PuertollanoR (2006) Two di-leucine motifs regulate trafficking of mucolipin-1 to lysosomes. Traffic7:337–353

[56] WakabayashiK, GustafsonAM, SidranskyE, GoldinE (2011) Mucolipidosis type IV: an update.Mol Genet Metab104:206–213

[57] Waller-EvansH, Lloyd-EvansE (2015) Regulation of TRPML1 function.Biochem Soc Trans43:442–446

[58] WangW, ZhangX, GaoQ, XuH (2014) TRPML1: an ion channel in the lysosome.Handb Exp Pharmacol222:631–645

[59] WeitzR, KohnG (1988) Clinical spectrum of mucolipidosis type IV.Pediatrics81:602–603

[60] WilkesM, MadejMG, KreuterL, RhinowD, HeinzV, De SanctisS, RuppelS, RichterRM, JoosF, GriebenM (2017) Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel Polycystin-2.Nat Struct Mol Biol24:123–130

[61] XuH, DellingM, LiL, DongX, ClaphamDE (2007) Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice.Proc Natl Acad Sci USA104:18321–18326

[62] ZeeviDA, FrumkinA, BachG (2007) TRPML and lysosomal function.Biochim Biophys Acta1772:851–858

[63] ZhangY (2008) I-TASSER server for protein 3D structure prediction.BMC Bioinform9:40

[64] ZhangX, LiX, XuH (2012) Phosphoinositide isoforms determine compartment-specific ion channel activity.Proc Natl Acad Sci USA109:11384–11389

[65] ZhengSQ, PalovcakE, ArmacheJP, VerbaKA, ChengY, AgardDA (2017) MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy.Nat Methods14:331–332

RIGHTS & PERMISSIONS

2017 The Author(s) 2017. This article is an open access publication