MADD4_CAEEL
ID MADD4_CAEEL Reviewed; 1045 AA.
AC P90884; I2HA89; Q8I4I1;
DT 20-DEC-2017, integrated into UniProtKB/Swiss-Prot.
DT 13-SEP-2004, sequence version 5.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Protein madd-4 {ECO:0000305};
DE AltName: Full=Punctin {ECO:0000303|PubMed:24896188};
DE Flags: Precursor;
GN Name=madd-4 {ECO:0000312|WormBase:F53B6.2a};
GN ORFNames=F53B6.2 {ECO:0000312|WormBase:F53B6.2a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239 {ECO:0000312|Proteomes:UP000001940};
RN [1] {ECO:0000312|Proteomes:UP000001940}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2 {ECO:0000312|Proteomes:UP000001940};
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2] {ECO:0000305}
RP ALTERNATIVE PROMOTER USAGE (ISOFORMS A AND B), FUNCTION, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, DOMAIN, DISRUPTION
RP PHENOTYPE, AND MUTAGENESIS OF ARG-398.
RX PubMed=22014523; DOI=10.1016/j.devcel.2011.07.020;
RA Seetharaman A., Selman G., Puckrin R., Barbier L., Wong E., D'Souza S.A.,
RA Roy P.J.;
RT "MADD-4 is a secreted cue required for midline-oriented guidance in
RT Caenorhabditis elegans.";
RL Dev. Cell 21:669-680(2011).
RN [3] {ECO:0000305}
RP ALTERNATIVE PROMOTER USAGE (ISOFORMS A AND B), ALTERNATIVE SPLICING
RP (ISOFORMS A AND C), FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=24896188; DOI=10.1038/nature13313;
RA Pinan-Lucarre B., Tu H., Pierron M., Cruceyra P.I., Zhan H., Stigloher C.,
RA Richmond J.E., Bessereau J.L.;
RT "C. elegans Punctin specifies cholinergic versus GABAergic identity of
RT postsynaptic domains.";
RL Nature 511:466-470(2014).
RN [4] {ECO:0000305}
RP FUNCTION, AND INTERACTION WITH EVA-1; UNC-40 AND UNC-5.
RX PubMed=25122090; DOI=10.1371/journal.pgen.1004521;
RA Chan K.K., Seetharaman A., Bagg R., Selman G., Zhang Y., Kim J., Roy P.J.;
RT "EVA-1 functions as an UNC-40 Co-receptor to enhance attraction to the
RT MADD-4 guidance cue in Caenorhabditis elegans.";
RL PLoS Genet. 10:E1004521-E1004521(2014).
RN [5] {ECO:0000305}
RP FUNCTION, INTERACTION WITH NLG-1 AND UNC-40, AND DISRUPTION PHENOTYPE.
RX PubMed=26028575; DOI=10.1016/j.neuron.2015.05.013;
RA Tu H., Pinan-Lucarre B., Ji T., Jospin M., Bessereau J.L.;
RT "C. elegans Punctin Clusters GABA(A) Receptors via Neuroligin Binding and
RT UNC-40/DCC Recruitment.";
RL Neuron 86:1407-1419(2015).
RN [6] {ECO:0000305}
RP FUNCTION, AND INTERACTION WITH NLG-1 AND NRX-1.
RX PubMed=26028574; DOI=10.1016/j.neuron.2015.05.015;
RA Maro G.S., Gao S., Olechwier A.M., Hung W.L., Liu M., Oezkan E., Zhen M.,
RA Shen K.;
RT "MADD-4/Punctin and Neurexin Organize C. elegans GABAergic Postsynapses
RT through Neuroligin.";
RL Neuron 86:1420-1432(2015).
CC -!- FUNCTION: Component of an extracellular matrix cue that is involved in
CC the guidance of dorsoventral midline migrations and in the
CC specification of postsynaptic domains at neuromuscular junctions (NMJs)
CC (PubMed:22014523, PubMed:24896188, PubMed:25122090, PubMed:26028575,
CC PubMed:26028574). Acts as a ligand for the netrin receptor unc-40 and
CC the neuroligin receptor nlg-1 (PubMed:22014523, PubMed:26028575,
CC PubMed:25122090, PubMed:24896188). Secreted by the dorsal and ventral
CC nerve cords to attract sensory axons and muscle membrane extensions
CC called muscle arms (PubMed:22014523). In parallel with unc-6 and slt-1,
CC involved in the netrin receptor unc-40 dependent guidance of the AVM
CC and PVM mechanosensory axons along the dorsal-ventral axis
CC (PubMed:22014523). The unc-40 coreceptor eva-1 is enhancing the
CC responsiveness of unc-40 to the madd-4 guidance cue to attract the
CC muscle arm extensions and AVM mechanosensory axons towards the
CC dorsoventral midline (PubMed:25122090). Acts as a synaptic organizer
CC and is required for the specification of inhibitory GABAergic and
CC excitatory cholinergic identities of postsynaptic domains at
CC neuromuscular junctions (NMJs) (PubMed:24896188, PubMed:26028575,
CC PubMed:26028574). Required for the recruitment of unc-40 to both
CC cholinergic and GABAergic NMJs (PubMed:26028575). Promotes the
CC clustering of ACh receptors and GABA(A) receptors at postsynaptic sites
CC during synaptogenesis (PubMed:24896188). The binding to the presynaptic
CC adhesion protein nrx-1 and to the neuroligin nlg-1 at postsynaptic
CC sites promotes clustering of GABAergic receptors at postsynaptic NMJs,
CC thereby contributing to normal GABAergic synaptic transmission
CC (PubMed:26028574). {ECO:0000269|PubMed:22014523,
CC ECO:0000269|PubMed:24896188, ECO:0000269|PubMed:25122090,
CC ECO:0000269|PubMed:26028574, ECO:0000269|PubMed:26028575}.
CC -!- FUNCTION: Isoform a and isoform c: Promotes the clustering of
CC acetylcholine receptors (AChR) at excitatory cholinergic synapses of
CC NMJs via the netrin receptor unc-40. {ECO:0000269|PubMed:24896188}.
CC -!- FUNCTION: [Isoform b]: Acts as a guidance cue in the attraction of
CC muscle membrane extensions (muscle arms) to the dorsal cord and in
CC cooperation with unc-6 to the ventral cord via the netrin receptor unc-
CC 40 and via the unc-40 coreceptor eva-1 (PubMed:22014523,
CC PubMed:25122090). Together with nrx-1, clusters netrin receptor unc-40
CC and neuroligin nlg-1 at postsynaptic sites of GABAergic NMJs, thereby
CC promoting the recruitment of GABA(A) receptors at GABAergic synapses
CC (PubMed:24896188, PubMed:26028575, PubMed:26028574). Prevents the
CC recruitment of GABAergic receptors to cholinergic synapses
CC (PubMed:24896188). {ECO:0000269|PubMed:22014523,
CC ECO:0000269|PubMed:24896188, ECO:0000269|PubMed:25122090,
CC ECO:0000269|PubMed:26028574, ECO:0000269|PubMed:26028575}.
CC -!- SUBUNIT: Interacts with eva-1 (via the SUEL-type lectin domain)
CC (PubMed:25122090). Interacts with unc-5 (PubMed:25122090). Interacts
CC with unc-40; the interaction is required for the localization of unc-40
CC to postsynaptic domains (PubMed:25122090, PubMed:26028575). Isoform a
CC forms homodimers and heterodimers with isoform b (PubMed:24896188).
CC Isoform b forms homodimers and heterodimers with isoform a
CC (PubMed:24896188). Isoform b interacts with nlg-1 (via extracellular
CC domain); the interaction is required for nlg-1 localization to
CC postsynaptic domains (PubMed:26028574, PubMed:26028575). Isoform b
CC interacts (via the Ig-like C2-type domain) with nrx-1 (via C-terminus)
CC (PubMed:26028574). {ECO:0000269|PubMed:24896188,
CC ECO:0000269|PubMed:25122090, ECO:0000269|PubMed:26028574,
CC ECO:0000269|PubMed:26028575}.
CC -!- SUBCELLULAR LOCATION: Cell projection, axon
CC {ECO:0000269|PubMed:22014523, ECO:0000269|PubMed:24896188}. Secreted
CC {ECO:0000269|PubMed:22014523, ECO:0000269|PubMed:24896188}. Synapse
CC {ECO:0000269|PubMed:24896188}. Secreted, extracellular space,
CC extracellular matrix {ECO:0000269|PubMed:22014523,
CC ECO:0000269|PubMed:24896188}. Note=Isoform b is secreted by cholinergic
CC and GABAergic motoneurons and localizes to excitatory cholinergic and
CC inhibitory GABAergic NMJs, whereas isoform a and isoform c are
CC exclusively secreted by cholinergic motoneurons and localize to
CC excitatory cholinergic NMJs. {ECO:0000269|PubMed:22014523,
CC ECO:0000269|PubMed:24896188}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=3;
CC Name=a {ECO:0000312|WormBase:F53B6.2a};
CC IsoId=P90884-1; Sequence=Displayed;
CC Name=b {ECO:0000312|WormBase:F53B6.2b};
CC IsoId=P90884-2; Sequence=VSP_059274;
CC Name=c {ECO:0000312|WormBase:F53B6.2c};
CC IsoId=P90884-3; Sequence=VSP_059275;
CC -!- TISSUE SPECIFICITY: Isoform a: Expressed in the commissural GABAergic
CC and cholinergic motor neurons in the first larval stage but only in the
CC cholinergic motor neurons in later larval stages and in adult animals
CC (PubMed:22014523). At the L1 larval stage, mainly localized at the
CC nerve ring and at the dorsal cord (PubMed:24896188). Isoform b:
CC Expressed in the commissural GABAergic and cholinergic motor neurons
CC whose cell bodies reside in the ventral nerve cord and which extend
CC axons into the ventral and dorsal nerve cord (PubMed:22014523,
CC PubMed:24896188). Also expressed in the head neurons RIA, RIC, lateral
CC IL1s, lateral IL2s, OLLs, RMEs and SABs, all of which extend axons into
CC the nerve ring (PubMed:22014523, PubMed:24896188). Expressed in the
CC embryogenic blast cells and the corresponding terminally differentiated
CC ventral cord motor neurons and head neurons (PubMed:22014523).
CC {ECO:0000269|PubMed:22014523, ECO:0000269|PubMed:24896188}.
CC -!- DEVELOPMENTAL STAGE: Isoform a: Expressed in larval stages L1 and L2
CC and in adult animals. Isoform b: Expressed in embryos, larval stages L1
CC and L2 and in adult animals. {ECO:0000269|PubMed:22014523}.
CC -!- DOMAIN: The Ig-like C2-type domain is required for the attraction of
CC the muscle arm extensions. {ECO:0000269|PubMed:22014523}.
CC -!- DISRUPTION PHENOTYPE: Disrupts the clustering of the cholinergic
CC receptor subunits unc-29, unc-38 and acr-16 and the GABAergic receptor
CC subunit unc-49 at postsynaptic domains of neuromuscular junctions
CC (NMJs), and the receptors are redistributed to extrasynaptic areas
CC (PubMed:24896188, PubMed:26028575). Loss of neuroligin receptor nlg-1
CC and netrin receptor unc-40 localization to NMJs (PubMed:26028575).
CC Isoform a and isoform c: Defects in AChR localization to cholinergic
CC synapses (PubMed:24896188). Decreased AChR-dependent currents triggered
CC by motoneuron stimulation (PubMed:24896188). Isoform b: Extensive
CC dorsal muscle arm extension defects and weaker ventral muscle arm
CC extension defects (PubMed:24896188, PubMed:22014523). Relocalization of
CC GABAergic receptors from GABAergic to cholinergic synapses
CC (PubMed:24896188, PubMed:26028575). Redistribution of the neuroligin
CC receptor nlg-1 from GABAergic to cholinergic NMJs (PubMed:26028575). In
CC a unc-6 mutant background, extensive ventral muscle arm extension
CC defects (PubMed:22014523). Loss of unc-40 localization at GABAergic
CC NMJs (PubMed:26028575). {ECO:0000269|PubMed:22014523,
CC ECO:0000269|PubMed:24896188, ECO:0000269|PubMed:26028575}.
CC -!- MISCELLANEOUS: [Isoform b]: Produced by alternative promoter usage.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform c]: Produced by alternative splicing of isoform
CC a. {ECO:0000305}.
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DR EMBL; BX284601; CAB03121.3; -; Genomic_DNA.
DR EMBL; BX284601; CAD56586.1; -; Genomic_DNA.
DR EMBL; BX284601; CCH63796.1; -; Genomic_DNA.
DR PIR; T22545; T22545.
DR RefSeq; NP_001250933.1; NM_001264004.1. [P90884-3]
DR RefSeq; NP_492405.3; NM_060004.4. [P90884-1]
DR RefSeq; NP_871884.1; NM_182084.5. [P90884-2]
DR AlphaFoldDB; P90884; -.
DR STRING; 6239.F53B6.2a; -.
DR PaxDb; P90884; -.
DR EnsemblMetazoa; F53B6.2a.1; F53B6.2a.1; WBGene00009958. [P90884-1]
DR EnsemblMetazoa; F53B6.2b.1; F53B6.2b.1; WBGene00009958. [P90884-2]
DR EnsemblMetazoa; F53B6.2c.1; F53B6.2c.1; WBGene00009958. [P90884-3]
DR GeneID; 172706; -.
DR KEGG; cel:CELE_F53B6.2; -.
DR UCSC; F53B6.2b; c. elegans.
DR CTD; 172706; -.
DR WormBase; F53B6.2a; CE36859; WBGene00009958; madd-4. [P90884-1]
DR WormBase; F53B6.2b; CE32429; WBGene00009958; madd-4. [P90884-2]
DR WormBase; F53B6.2c; CE32428; WBGene00009958; madd-4. [P90884-3]
DR eggNOG; KOG3538; Eukaryota.
DR InParanoid; P90884; -.
DR OMA; MEDELLW; -.
DR OrthoDB; 38261at2759; -.
DR PhylomeDB; P90884; -.
DR Reactome; R-CEL-5173214; O-glycosylation of TSR domain-containing proteins.
DR PRO; PR:P90884; -.
DR Proteomes; UP000001940; Chromosome I.
DR Bgee; WBGene00009958; Expressed in larva and 3 other tissues.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IDA:WormBase.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
DR GO; GO:0004222; F:metalloendopeptidase activity; IEA:InterPro.
DR GO; GO:0005102; F:signaling receptor binding; IPI:WormBase.
DR GO; GO:0033563; P:dorsal/ventral axon guidance; IGI:WormBase.
DR GO; GO:0030198; P:extracellular matrix organization; IEA:InterPro.
DR GO; GO:0050808; P:synapse organization; IMP:WormBase.
DR Gene3D; 2.20.100.10; -; 7.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR013273; ADAMTS/ADAMTS-like.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR010909; PLAC.
DR InterPro; IPR000884; TSP1_rpt.
DR InterPro; IPR036383; TSP1_rpt_sf.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF00090; TSP_1; 1.
DR PRINTS; PR01857; ADAMTSFAMILY.
DR SMART; SM00409; IG; 1.
DR SMART; SM00408; IGc2; 1.
DR SMART; SM00209; TSP1; 9.
DR SUPFAM; SSF48726; SSF48726; 1.
DR SUPFAM; SSF82895; SSF82895; 9.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS50900; PLAC; 1.
DR PROSITE; PS50092; TSP1; 6.
PE 1: Evidence at protein level;
KW Alternative promoter usage; Alternative splicing; Cell projection;
KW Disulfide bond; Extracellular matrix; Glycoprotein; Immunoglobulin domain;
KW Reference proteome; Repeat; Secreted; Signal; Synapse.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT CHAIN 24..1045
FT /note="Protein madd-4"
FT /evidence="ECO:0000255"
FT /id="PRO_5004161775"
FT DOMAIN 24..71
FT /note="TSP type-1 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DOMAIN 236..292
FT /note="TSP type-1 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DOMAIN 294..510
FT /note="TSP type-1 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DOMAIN 512..572
FT /note="TSP type-1 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DOMAIN 576..635
FT /note="TSP type-1 5"
FT /evidence="ECO:0000255"
FT DOMAIN 637..732
FT /note="Ig-like C2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DOMAIN 811..873
FT /note="TSP type-1 6"
FT /evidence="ECO:0000255"
FT DOMAIN 932..990
FT /note="TSP type-1 7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DOMAIN 1004..1041
FT /note="PLAC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00233"
FT CARBOHYD 268
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 280
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 730
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 781
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 899
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 906
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 35..65
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 39..70
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 50..55
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00210"
FT DISULFID 674..722
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 1..351
FT /note="MKCSYTVVFLLFYLLIASFHVDALSWAAWSPWSSCTKTCGGGVSRQLRRCLT
FT SKCSGESVRFKVCAQKTCESKSRLARDTICGGEEIVSRGQCEVVCRSRLTGANFLWRVD
FT DGTPCQAATSRAVCSKGSCQIVGCDGLISSSFRFDACGVCGGRGDTCDNGKFIWKVSEE
FT YTACASNCDDIVDWSGAGRSIASTSQPIVVCVNAITGRVVPEKLCADKLRPKVEARPCP
FT MLICPSRCRWMAADWTECVPHCGEGTRKREVYCVQTAHNVTVHVPDTFCENGTRPAAEE
FT NCVSTSCGRWEAGKWSKCTASCGQGVRRRHVACVGGSDCDEGGRPRQETTCYAGIPCSI
FT ATNS -> MLPLLLILSAPLGVSAF (in isoform b)"
FT /evidence="ECO:0000305"
FT /id="VSP_059274"
FT VAR_SEQ 237..238
FT /note="Missing (in isoform c)"
FT /evidence="ECO:0000305"
FT /id="VSP_059275"
FT MUTAGEN 398
FT /note="R->H: Disrupts the attraction of the muscle arm
FT extensions."
FT /evidence="ECO:0000269|PubMed:22014523"
SQ SEQUENCE 1045 AA; 116125 MW; F78269D1D50228B1 CRC64;
MKCSYTVVFL LFYLLIASFH VDALSWAAWS PWSSCTKTCG GGVSRQLRRC LTSKCSGESV
RFKVCAQKTC ESKSRLARDT ICGGEEIVSR GQCEVVCRSR LTGANFLWRV DDGTPCQAAT
SRAVCSKGSC QIVGCDGLIS SSFRFDACGV CGGRGDTCDN GKFIWKVSEE YTACASNCDD
IVDWSGAGRS IASTSQPIVV CVNAITGRVV PEKLCADKLR PKVEARPCPM LICPSRCRWM
AADWTECVPH CGEGTRKREV YCVQTAHNVT VHVPDTFCEN GTRPAAEENC VSTSCGRWEA
GKWSKCTASC GQGVRRRHVA CVGGSDCDEG GRPRQETTCY AGIPCSIATN SLDWNDRAYL
DGNTFGSMDN HNDWQAPRLV AGEWSTCSST CGTGVMSRTV ECVAVNPISS APIKLPMSEC
QDQEQPKLFE SCEVRSCPLQ EDSKLSEDEA PYQWRYGDWT QCSASCLGGK QKAALKCIQV
STGKSVQWSQ CDARRRPPEK SRPCNQHPCP PFWLTSKYSD CSMSCGSGTA RRSVKCAQTV
SKTDGADAHI VLRDDRCHFK KPQETETCNV VACPATWVTA QWTECSRSCD SGERRRQVWC
EIRDSRGKTQ RRPDVECDAN TKPQTVEVCS FGSCSRPELL SNRVFEQNAE QKKLTLGIGG
VATLYQGTSI KIKCPAKKFD KKKIYWKKNG KKIKNDAHIK VSANGNLRVF HARMEDAGVY
ECFTDRLQGN VTLNFKYRDF PASRVDLAPK PQIPSTKNRQ RVQVSKEDVL REQASVLHKM
NVSLIEALLT APNDEKAREQ LRKYGNELVA RWDIGHWSEC RQKTCHVAGY QARGISCKVT
FHGEIRNVDN SICESLASVR PPETRPCHRE DCPRWEASQW SECSSQRCVS SMLAQKRRNV
TCRFTNGTSV DIQHCDITNR PATTMDCPNQ NCKAEWRTSD WGSCSSECGT GGVQLRLLSC
VWISSGRPAG RNCEQMRRPH SARACVADEP LPPCMPTASA LYQRDASCQD QSRFCDIIKL
FHSCDSLEVR QKCCSTCTFV ERKKF
