CBLN4_MOUSE
ID CBLN4_MOUSE Reviewed; 198 AA.
AC Q8BME9; Q505H5; Q8BMF0;
DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=Cerebellin-4;
DE AltName: Full=Cerebellin-like glycoprotein 1;
DE Flags: Precursor;
GN Name=Cbln4; Synonyms=Cblnl1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J; TISSUE=Testis;
RX PubMed=12617826; DOI=10.1016/s1567-133x(02)00022-4;
RA Menke D.B., Page D.C.;
RT "Sexually dimorphic gene expression in the developing mouse gonad.";
RL Gene Expr. Patterns 2:359-367(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Olfactory bulb;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain, and Embryonic brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=16930405; DOI=10.1111/j.1460-9568.2006.04950.x;
RA Miura E., Iijima T., Yuzaki M., Watanabe M.;
RT "Distinct expression of Cbln family mRNAs in developing and adult mouse
RT brains.";
RL Eur. J. Neurosci. 24:750-760(2006).
RN [6]
RP FUNCTION, SELF-ASSOCIATION, SUBCELLULAR LOCATION, AND INTERACTION WITH
RP CBLN1; CBLN2 AND CBLN3.
RX PubMed=17030622; DOI=10.1128/mcb.01161-06;
RA Bao D., Pang Z., Morgan M.A., Parris J., Rong Y., Li L., Morgan J.I.;
RT "Cbln1 is essential for interaction-dependent secretion of cbln3.";
RL Mol. Cell. Biol. 26:9327-9337(2006).
RN [7]
RP OLIGOMERIZATION WITH CBLN1; CBLN2; CBLN3 AND CBLN4, SUBCELLULAR LOCATION,
RP GLYCOSYLATION AT ASN-26 AND ASN-85, AND MUTAGENESIS OF ASN-26 AND ASN-85.
RX PubMed=17331201; DOI=10.1111/j.1460-9568.2007.05361.x;
RA Iijima T., Miura E., Matsuda K., Kamekawa Y., Watanabe M., Yuzaki M.;
RT "Characterization of a transneuronal cytokine family Cbln - regulation of
RT secretion by heteromeric assembly.";
RL Eur. J. Neurosci. 25:1049-1057(2007).
RN [8]
RP INTERACTION WITH DCC; NRXN1; NRXN2 AND NRXN3, LACK OF INTERACTION WITH
RP GRID1 AND GRID2, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=22220752; DOI=10.1111/j.1471-4159.2012.07648.x;
RA Wei P., Pattarini R., Rong Y., Guo H., Bansal P.K., Kusnoor S.V.,
RA Deutch A.Y., Parris J., Morgan J.I.;
RT "The Cbln family of proteins interact with multiple signaling pathways.";
RL J. Neurochem. 121:717-729(2012).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=25534236; DOI=10.1016/j.neurobiolaging.2014.11.006;
RA Chacon P.J., del Marco A., Arevalo A., Dominguez-Gimenez P.,
RA Garcia-Segura L.M., Rodriguez-Tebar A.;
RT "Cerebellin 4, a synaptic protein, enhances inhibitory activity and
RT resistance of neurons to amyloid-beta toxicity.";
RL Neurobiol. Aging 36:1057-1071(2015).
RN [10]
RP GLYCOSYLATION AT ASN-26 AND ASN-85, INTERACTION WITH NRXN1; NRXN3 AND DCC,
RP LACK OF INTERACTION WITH NEO1; GRID1 AND GRID2, SUBUNIT, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF ASN-26 AND ASN-85.
RX PubMed=29782851; DOI=10.1016/j.brainres.2018.05.022;
RA Rong Y., Bansal P.K., Wei P., Guo H., Correia K., Parris J., Morgan J.I.;
RT "Glycosylation of Cblns attenuates their receptor binding.";
RL Brain Res. 1694:129-139(2018).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29691328; DOI=10.1523/jneurosci.0360-18.2018;
RA Seigneur E., Suedhof T.C.;
RT "Genetic Ablation of All Cerebellins Reveals Synapse Organizer Functions in
RT Multiple Regions Throughout the Brain.";
RL J. Neurosci. 38:4774-4790(2018).
RN [12]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=30287486; DOI=10.1073/pnas.1811086115;
RA Seigneur E., Polepalli J.S., Suedhof T.C.;
RT "Cbln2 and Cbln4 are expressed in distinct medial habenula-interpeduncular
RT projections and contribute to different behavioral outputs.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E10235-E10244(2018).
RN [13]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=30679375; DOI=10.1126/science.aau8977;
RA Favuzzi E., Deogracias R., Marques-Smith A., Maeso P., Jezequel J.,
RA Exposito-Alonso D., Balia M., Kroon T., Hinojosa A.J., Maraver E.F.,
RA Rico B.;
RT "Distinct molecular programs regulate synapse specificity in cortical
RT inhibitory circuits.";
RL Science 363:413-417(2019).
CC -!- FUNCTION: Acts as a synaptic organizer in specific subsets of neurons
CC in the brain (PubMed:29691328). Essential for the formation and
CC maintenance of inhibitory GABAergic synapses (PubMed:25534236).
CC Promotes the development of dendrite-targeting inhibitory GABAergic
CC synapses made by somatostatin-positive interneurons (PubMed:30679375).
CC May contribute to the function of ventral medial habenula region of the
CC brain implicated in the regulation of anxiety-related behaviors
CC (PubMed:30287486). May play a role in CBLN3 export from the endoplasmic
CC reticulum and secretion (PubMed:17030622).
CC {ECO:0000269|PubMed:17030622, ECO:0000269|PubMed:25534236,
CC ECO:0000269|PubMed:29691328, ECO:0000269|PubMed:30287486,
CC ECO:0000269|PubMed:30679375}.
CC -!- SUBUNIT: Homohexamer; disulfide-linked homotrimers. The trimers are
CC assembled via the globular C1q domains. The trimers associate via N-
CC terminal cysteine residues to form disulfide-linked hexamers (By
CC similarity). May form oligomers with CBLN1, CBLN2 and CBLN3 prior to
CC secretion (PubMed:17030622, PubMed:29782851). Once secreted, does not
CC interact with other CBLN family members (PubMed:17030622). Strongly
CC interacts with DCC in a NTN1-displaceable fashion (PubMed:22220752,
CC PubMed:29782851). Weakly binds to NRXN1 and NRXN2 long and short
CC isoforms produced by alternative promoter usage (PubMed:22220752,
CC PubMed:29782851). Interaction with NRXN3 short isoform is hardly
CC detectable; no interaction at all with NRXN3 long isoform
CC (PubMed:22220752, PubMed:29782851). Does not interact with NEO1, GRID1
CC and GRID2 (PubMed:22220752, PubMed:29782851).
CC {ECO:0000250|UniProtKB:Q9R171, ECO:0000269|PubMed:17030622,
CC ECO:0000269|PubMed:22220752, ECO:0000269|PubMed:29782851}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:17030622,
CC ECO:0000269|PubMed:17331201, ECO:0000269|PubMed:29782851}. Synapse
CC {ECO:0000269|PubMed:25534236}. Note=Detected at GABAergic synapses.
CC {ECO:0000269|PubMed:25534236}.
CC -!- TISSUE SPECIFICITY: Expressed in brain with high levels in particular
CC thalamic nuclei. In the thalamus, predominantly expressed in neurons
CC within the parafascicular nucleus. Found in the hippocampus, mostly in
CC the dendrites and somata of pyramidal neurons (at protein level). Very
CC low or no expression in most other brain regions. Highly expressed in
CC the ventral medial habenula. {ECO:0000269|PubMed:16930405,
CC ECO:0000269|PubMed:22220752, ECO:0000269|PubMed:25534236,
CC ECO:0000269|PubMed:30287486}.
CC -!- DEVELOPMENTAL STAGE: In the developing brain, expressed as early as 10-
CC 13 dpc. Expression level peaks at 18 dpc and gradually decreases
CC afterwards. Expressed in developing somatostatin-positive basket cells.
CC {ECO:0000269|PubMed:16930405, ECO:0000269|PubMed:30679375}.
CC -!- PTM: Sialoglycoprotein. {ECO:0000269|PubMed:29782851}.
CC -!- DISRUPTION PHENOTYPE: Mutant animals are fertile, have normal life
CC spans and have no overt anatomical abnormalities (PubMed:22220752).
CC They have a normal corpus callosum, hippocampal commisure and pontine
CC nucleus and no other gross neuroanatomical abnormalities
CC (PubMed:22220752). Mice exhibit increased anxiety-related behavior
CC (PubMed:30287486). Triple CBLN1, CBLN2 and CBLN4 knockout mice exhibit
CC impairments in sensory processing and sensorimotor gating, in addition
CC to severe motor deficits, seizures and reduced synapse density in the
CC hippocampus of aging mice (PubMed:29691328).
CC {ECO:0000269|PubMed:22220752, ECO:0000269|PubMed:29691328,
CC ECO:0000269|PubMed:30287486}.
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DR EMBL; AY134663; AAN08614.1; -; mRNA.
DR EMBL; AK032406; BAC27855.1; -; mRNA.
DR EMBL; AK032621; BAC27954.1; -; mRNA.
DR EMBL; CH466551; EDL06594.1; -; Genomic_DNA.
DR EMBL; BC094540; AAH94540.1; -; mRNA.
DR EMBL; BC132025; AAI32026.1; -; mRNA.
DR EMBL; BC132027; AAI32028.1; -; mRNA.
DR CCDS; CCDS17126.1; -.
DR RefSeq; NP_783439.1; NM_175631.3.
DR PDB; 5H4B; X-ray; 2.80 A; A=25-198.
DR PDBsum; 5H4B; -.
DR AlphaFoldDB; Q8BME9; -.
DR SMR; Q8BME9; -.
DR BioGRID; 230797; 2.
DR STRING; 10090.ENSMUSP00000085263; -.
DR GlyConnect; 2207; 2 N-Linked glycans (1 site).
DR GlyGen; Q8BME9; 2 sites, 2 N-linked glycans (1 site).
DR iPTMnet; Q8BME9; -.
DR PhosphoSitePlus; Q8BME9; -.
DR MaxQB; Q8BME9; -.
DR PaxDb; Q8BME9; -.
DR PRIDE; Q8BME9; -.
DR ProteomicsDB; 265345; -.
DR Antibodypedia; 28817; 114 antibodies from 27 providers.
DR DNASU; 228942; -.
DR Ensembl; ENSMUST00000087950; ENSMUSP00000085263; ENSMUSG00000067578.
DR GeneID; 228942; -.
DR KEGG; mmu:228942; -.
DR UCSC; uc008ock.1; mouse.
DR CTD; 140689; -.
DR MGI; MGI:2154433; Cbln4.
DR VEuPathDB; HostDB:ENSMUSG00000067578; -.
DR eggNOG; ENOG502QV08; Eukaryota.
DR GeneTree; ENSGT00940000159728; -.
DR HOGENOM; CLU_001074_8_2_1; -.
DR InParanoid; Q8BME9; -.
DR OMA; PTTDWKA; -.
DR OrthoDB; 1398761at2759; -.
DR PhylomeDB; Q8BME9; -.
DR TreeFam; TF329591; -.
DR BioGRID-ORCS; 228942; 1 hit in 71 CRISPR screens.
DR PRO; PR:Q8BME9; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q8BME9; protein.
DR Bgee; ENSMUSG00000067578; Expressed in habenula and 96 other tissues.
DR Genevisible; Q8BME9; MM.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0098982; C:GABA-ergic synapse; IDA:UniProtKB.
DR GO; GO:0045202; C:synapse; IBA:GO_Central.
DR GO; GO:1904862; P:inhibitory synapse assembly; IMP:UniProtKB.
DR GO; GO:0099558; P:maintenance of synapse structure; IBA:GO_Central.
DR GO; GO:0009306; P:protein secretion; IDA:MGI.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR001073; C1q_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR Pfam; PF00386; C1q; 1.
DR PRINTS; PR00007; COMPLEMNTC1Q.
DR SMART; SM00110; C1Q; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS50871; C1Q; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disulfide bond; Glycoprotein; Reference proteome; Secreted;
KW Sialic acid; Signal; Synapse.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..198
FT /note="Cerebellin-4"
FT /id="PRO_0000003557"
FT DOMAIN 63..198
FT /note="C1q"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00368"
FT CARBOHYD 26
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17331201"
FT CARBOHYD 85
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17331201"
FT DISULFID 37
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT DISULFID 41
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT MUTAGEN 26
FT /note="N->Q: No effect on its ability to form homohexameric
FT or heteromeric complexes with other CBLN family members.
FT Increased interaction with NRXN1, NRXN3 and DCC. Shows
FT interaction with NEO1, GRID1 and GRID2. Total loss of N-
FT glycosylation; when associated with Q-85."
FT /evidence="ECO:0000269|PubMed:17331201,
FT ECO:0000269|PubMed:29782851"
FT MUTAGEN 85
FT /note="N->Q: No effect on its ability to form homohexameric
FT or heteromeric complexes with other CBLN family members.
FT Increased interaction with NRXN1, NRXN3 and DCC. Shows
FT interaction with NEO1, GRID1 and GRID2. Total loss of N-
FT glycosylation; when associated with Q-26."
FT /evidence="ECO:0000269|PubMed:17331201,
FT ECO:0000269|PubMed:29782851"
FT CONFLICT 112
FT /note="P -> T (in Ref. 1; BAC27855)"
FT /evidence="ECO:0000305"
FT STRAND 69..73
FT /evidence="ECO:0007829|PDB:5H4B"
FT HELIX 82..87
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 94..99
FT /evidence="ECO:0007829|PDB:5H4B"
FT TURN 105..107
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 108..110
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 112..127
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 132..138
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 141..148
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 155..166
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 171..179
FT /evidence="ECO:0007829|PDB:5H4B"
FT STRAND 189..197
FT /evidence="ECO:0007829|PDB:5H4B"
SQ SEQUENCE 198 AA; 21609 MW; 5A35ACC1354C70D6 CRC64;
MGSARRALSV VPAVLLILVL PVWAQNDTEP IVLEGKCLVV CDSNPATDSK GSSSSPLGIS
VRAANSKVAF SAVRSTNHEP SEMSNKTRII YFDQILVNVG NFFTLESVFV APRKGIYSFS
FHVIKVYQSQ TIQVNLMLNG KPVISAFAGD KDVTREAATN GVLLYLDKED KVYLKLEKGN
LLGGWQYSTF SGFLVFPL
