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CBLN1_HUMAN
ID   CBLN1_HUMAN             Reviewed;         193 AA.
AC   P23435; B2RAN9; P02682; Q52M09;
DT   01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1991, sequence version 1.
DT   03-AUG-2022, entry version 171.
DE   RecName: Full=Cerebellin-1;
DE   AltName: Full=Precerebellin;
DE   Contains:
DE     RecName: Full=Cerebellin;
DE              Short=CER;
DE   Contains:
DE     RecName: Full=[des-Ser1]-cerebellin;
DE   Flags: Precursor;
GN   Name=CBLN1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=1704129; DOI=10.1073/pnas.88.3.1069;
RA   Urade Y., Oberdick J., Molinar-Rode R., Morgan J.I.;
RT   "Precerebellin is a cerebellum-specific protein with similarity to the
RT   globular domain of complement C1q B chain.";
RL   Proc. Natl. Acad. Sci. U.S.A. 88:1069-1073(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=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   PROTEIN SEQUENCE OF 57-72 (CEREBELLIN AND [DES-SER1]-CEREBELLIN).
RC   TISSUE=Cerebellum;
RX   PubMed=2760624; DOI=10.1111/j.1471-4159.1989.tb11787.x;
RA   Yiangou Y., Burnet P., Nikou G., Chrysanthou B.J., Bloom S.R.;
RT   "Purification and characterisation of cerebellins from human and porcine
RT   cerebellum.";
RL   J. Neurochem. 53:886-889(1989).
RN   [6] {ECO:0007744|PDB:5KC5, ECO:0007744|PDB:5KC6, ECO:0007744|PDB:5KC7, ECO:0007744|PDB:5KCA}
RP   X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 58-193, GLYCOSYLATION AT ASN-79,
RP   MUTAGENESIS OF CYS-34; CYS-38; TYR-122; ARG-124 AND ASP-147, SUBUNIT,
RP   INTERACTION WITH NRXN1 AND GRID2, FUNCTION, AND REGION.
RX   PubMed=27418511; DOI=10.1126/science.aae0104;
RA   Elegheert J., Kakegawa W., Clay J.E., Shanks N.F., Behiels E., Matsuda K.,
RA   Kohda K., Miura E., Rossmann M., Mitakidis N., Motohashi J., Chang V.T.,
RA   Siebold C., Greger I.H., Nakagawa T., Yuzaki M., Aricescu A.R.;
RT   "Structural basis for integration of GluD receptors within synaptic
RT   organizer complexes.";
RL   Science 353:295-299(2016).
CC   -!- FUNCTION: Required for synapse integrity and synaptic plasticity.
CC       During cerebellar synapse formation, essential for the matching and
CC       maintenance of pre- and post-synaptic elements at parallel fiber-
CC       Purkinje cell synapses, the establishment of the proper pattern of
CC       climbing fiber-Purkinje cell innervation, and induction of long-term
CC       depression at parallel fiber-Purkinje cell synapses. Plays a role as a
CC       synaptic organizer that acts bidirectionally on both pre- and post-
CC       synaptic components. On the one hand induces accumulation of synaptic
CC       vesicles in the pre-synaptic part by binding with NRXN1 and in other
CC       hand induces clustering of GRID2 and its associated proteins at the
CC       post-synaptic site through association of GRID2. NRXN1-CBLN1-GRID2
CC       complex directly induces parallel fiber protrusions that encapsulate
CC       spines of Purkinje cells leading to accumulation of GRID2 and synaptic
CC       vesicles. Required for CBLN3 export from the endoplasmic reticulum and
CC       secretion (By similarity). NRXN1-CBLN1-GRID2 complex mediates the D-
CC       Serine-dependent long term depression signals and AMPA receptor
CC       endocytosis (PubMed:27418511). Essential for long-term maintenance but
CC       not establishment of excitatory synapses (By similarity). Inhibits the
CC       formation and function of inhibitory GABAergic synapses in cerebellar
CC       Purkinje cells (By similarity). {ECO:0000250|UniProtKB:Q9R171,
CC       ECO:0000269|PubMed:27418511}.
CC   -!- FUNCTION: The cerebellin peptide exerts neuromodulatory functions.
CC       Directly stimulates norepinephrine release via the adenylate
CC       cyclase/PKA-dependent signaling pathway; and indirectly enhances
CC       adrenocortical secretion in vivo, through a paracrine mechanism
CC       involving medullary catecholamine release (By similarity).
CC       {ECO:0000250|UniProtKB:P63182}.
CC   -!- SUBUNIT: Homohexamer; disulfide-linked homotrimers. The trimers
CC       associate via N-terminal cysteine residues to form disulfide-linked
CC       hexamers (PubMed:27418511). May form oligomers with CBLN2, CBLN3 AND
CC       CBLN4 prior to secretion. Once secreted, does not interact with other
CC       CBLN family members. Interacts with GRID1 (By similarity). Interacts
CC       with NRXN1 and NRXN2 long (alpha) and short (beta) isoforms produced by
CC       alternative promoter usage. Competes with NLGN1 for NRXN1-binding.
CC       Weakly interacts with NRXN3 short isoform and not at all with NRXN3
CC       long isoform (PubMed:27418511). Interacts (via C1q domain) with GRID2;
CC       GRID2-binding is calcium-independent; CBLN1 hexamers anchor GRID2 N-
CC       terminal domain dimers to monomeric NRXN1 isoform beta; promotes
CC       synaptogenesis and mediates the D-Serine-dependent long term depression
CC       signals and AMPA receptor endocytosis (PubMed:27418511). Interacts with
CC       OTOL1 (By similarity). {ECO:0000250|UniProtKB:Q9R171,
CC       ECO:0000269|PubMed:27418511}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q9R171}.
CC       Postsynaptic cell membrane {ECO:0000250|UniProtKB:Q9R171}.
CC   -!- TISSUE SPECIFICITY: In the Purkinje cells postsynaptic structures. In
CC       the cerebellum, cerebellin is much less abundant than [des-Ser1]-
CC       cerebellin.
CC   -!- DEVELOPMENTAL STAGE: Low at birth, the cerebellin concentration
CC       increases between day 5 and 15, and reaches peak values between day 21
CC       and 56.
CC   -!- PTM: The proteolytic processing to yield cerebellin seems to occur
CC       either prior to the secretion by presynaptic neurons and subsequent
CC       oligomerization or in some other location after release of the mature
CC       protein. {ECO:0000250|UniProtKB:Q9R171}.
CC   -!- PTM: Sialoglycoprotein. {ECO:0000250|UniProtKB:Q9R171}.
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DR   EMBL; M58583; AAA35676.1; -; mRNA.
DR   EMBL; AK314276; BAG36936.1; -; mRNA.
DR   EMBL; CH471092; EAW82731.1; -; Genomic_DNA.
DR   EMBL; BC093692; AAH93692.1; -; mRNA.
DR   EMBL; BC093718; AAH93718.1; -; mRNA.
DR   CCDS; CCDS10736.1; -.
DR   PIR; A37873; A37873.
DR   PIR; PL0124; PL0124.
DR   RefSeq; NP_004343.1; NM_004352.3.
DR   PDB; 5KC5; X-ray; 2.35 A; A=58-193.
DR   PDB; 5KC6; X-ray; 2.80 A; A/B/C=24-193.
DR   PDB; 5KC7; X-ray; 7.04 A; A/B/C/D=24-193.
DR   PDB; 5KCA; X-ray; 3.10 A; A=57-193.
DR   PDBsum; 5KC5; -.
DR   PDBsum; 5KC6; -.
DR   PDBsum; 5KC7; -.
DR   PDBsum; 5KCA; -.
DR   AlphaFoldDB; P23435; -.
DR   SMR; P23435; -.
DR   STRING; 9606.ENSP00000219197; -.
DR   GlyConnect; 2026; 1 N-Linked glycan (1 site).
DR   GlyGen; P23435; 4 sites, 2 N-linked glycans (1 site), 1 O-linked glycan (1 site).
DR   iPTMnet; P23435; -.
DR   PhosphoSitePlus; P23435; -.
DR   BioMuta; CBLN1; -.
DR   DMDM; 116114; -.
DR   MassIVE; P23435; -.
DR   PaxDb; P23435; -.
DR   PeptideAtlas; P23435; -.
DR   PRIDE; P23435; -.
DR   ProteomicsDB; 54094; -.
DR   Antibodypedia; 14491; 220 antibodies from 32 providers.
DR   DNASU; 869; -.
DR   Ensembl; ENST00000219197.11; ENSP00000219197.5; ENSG00000102924.12.
DR   Ensembl; ENST00000536749.1; ENSP00000444651.1; ENSG00000102924.12.
DR   GeneID; 869; -.
DR   KEGG; hsa:869; -.
DR   MANE-Select; ENST00000219197.11; ENSP00000219197.5; NM_004352.4; NP_004343.1.
DR   UCSC; uc002efq.4; human.
DR   CTD; 869; -.
DR   DisGeNET; 869; -.
DR   GeneCards; CBLN1; -.
DR   HGNC; HGNC:1543; CBLN1.
DR   HPA; ENSG00000102924; Group enriched (brain, testis).
DR   MIM; 600432; gene.
DR   neXtProt; NX_P23435; -.
DR   OpenTargets; ENSG00000102924; -.
DR   PharmGKB; PA26118; -.
DR   VEuPathDB; HostDB:ENSG00000102924; -.
DR   eggNOG; ENOG502QVN9; Eukaryota.
DR   GeneTree; ENSGT00940000159811; -.
DR   HOGENOM; CLU_001074_8_2_1; -.
DR   InParanoid; P23435; -.
DR   OMA; NRTMLIY; -.
DR   OrthoDB; 1398761at2759; -.
DR   PhylomeDB; P23435; -.
DR   TreeFam; TF329591; -.
DR   PathwayCommons; P23435; -.
DR   BioGRID-ORCS; 869; 71 hits in 1060 CRISPR screens.
DR   GenomeRNAi; 869; -.
DR   Pharos; P23435; Tbio.
DR   PRO; PR:P23435; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; P23435; protein.
DR   Bgee; ENSG00000102924; Expressed in cerebellar cortex and 102 other tissues.
DR   ExpressionAtlas; P23435; baseline and differential.
DR   Genevisible; P23435; HS.
DR   GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR   GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR   GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR   GO; GO:0098978; C:glutamatergic synapse; IBA:GO_Central.
DR   GO; GO:0098688; C:parallel fiber to Purkinje cell synapse; IEA:Ensembl.
DR   GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB.
DR   GO; GO:0045202; C:synapse; IBA:GO_Central.
DR   GO; GO:0043083; C:synaptic cleft; IBA:GO_Central.
DR   GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR   GO; GO:0021707; P:cerebellar granule cell differentiation; ISS:BHF-UCL.
DR   GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
DR   GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR   GO; GO:0007157; P:heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; ISS:BHF-UCL.
DR   GO; GO:0099558; P:maintenance of synapse structure; ISS:UniProtKB.
DR   GO; GO:0090394; P:negative regulation of excitatory postsynaptic potential; IMP:UniProtKB.
DR   GO; GO:1905703; P:negative regulation of inhibitory synapse assembly; ISS:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR   GO; GO:1900454; P:positive regulation of long-term synaptic depression; IMP:UniProtKB.
DR   GO; GO:0051965; P:positive regulation of synapse assembly; IEA:Ensembl.
DR   GO; GO:0009306; P:protein secretion; IEA:Ensembl.
DR   GO; GO:0099151; P:regulation of postsynaptic density assembly; IEA:Ensembl.
DR   GO; GO:1905606; P:regulation of presynapse assembly; IEA:Ensembl.
DR   GO; GO:0007416; P:synapse assembly; IEA:Ensembl.
DR   GO; GO:0050808; P:synapse organization; ISS:UniProtKB.
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; Cell membrane; Direct protein sequencing; Disulfide bond;
KW   Glycoprotein; Membrane; Postsynaptic cell membrane; Reference proteome;
KW   Secreted; Sialic acid; Signal; Synapse.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   CHAIN           22..193
FT                   /note="Cerebellin-1"
FT                   /id="PRO_0000274209"
FT   PEPTIDE         57..72
FT                   /note="Cerebellin"
FT                   /id="PRO_0000003546"
FT   PEPTIDE         58..72
FT                   /note="[des-Ser1]-cerebellin"
FT                   /id="PRO_0000274210"
FT   DOMAIN          57..193
FT                   /note="C1q"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00368"
FT   REGION          34..38
FT                   /note="Essential for interaction with NRXN1 and linker of
FT                   two C1q trimers into disulfide-linked hexamers"
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   REGION          62..193
FT                   /note="Necessary for interaction with CBLN3, and
FT                   homotrimerization"
FT                   /evidence="ECO:0000250|UniProtKB:Q9R171"
FT   REGION          122..147
FT                   /note="Essential for interaction with GRID2"
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   CARBOHYD        23
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        79
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:27418511,
FT                   ECO:0007744|PDB:5KC5, ECO:0007744|PDB:5KC6"
FT   DISULFID        34
FT                   /note="Interchain"
FT                   /evidence="ECO:0000250|UniProtKB:Q9R171"
FT   DISULFID        38
FT                   /note="Interchain"
FT                   /evidence="ECO:0000250|UniProtKB:Q9R171"
FT   MUTAGEN         34
FT                   /note="C->S: Abolishes hexamer formation; when associated
FT                   with S-38. Abolishes interaction with NRXN1; when
FT                   associated with S-38. Abolishes GRID2 interaction; when
FT                   associated with S-38."
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   MUTAGEN         38
FT                   /note="C->S: Abolishes hexamer formation; when associated
FT                   with S-34. Abolishes interaction with NRXN1 isoform 3B;
FT                   when associated with S-34. Abolishes GRID2 interaction.;
FT                   when associated with S-34."
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   MUTAGEN         122
FT                   /note="Y->A: Abolishes GRID2 interaction.; when associated
FT                   with A-124 and A-147."
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   MUTAGEN         124
FT                   /note="R->A: Abolishes GRID2 interaction.; when associated
FT                   with A-122 and A-147."
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   MUTAGEN         147
FT                   /note="D->A: Abolishes GRID2 interaction.; when associated
FT                   with A-122 and A-124."
FT                   /evidence="ECO:0000269|PubMed:27418511"
FT   STRAND          63..67
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   HELIX           78..81
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          87..93
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   TURN            99..102
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          103..105
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          107..120
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          127..133
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          136..143
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          147..149
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          151..161
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          166..174
FT                   /evidence="ECO:0007829|PDB:5KC5"
FT   STRAND          184..192
FT                   /evidence="ECO:0007829|PDB:5KC5"
SQ   SEQUENCE   193 AA;  21097 MW;  D542FC7987E401A5 CRC64;
     MLGVLELLLL GAAWLAGPAR GQNETEPIVL EGKCLVVCDS NPTSDPTGTA LGISVRSGSA
     KVAFSAIRST NHEPSEMSNR TMIIYFDQVL VNIGNNFDSE RSTFIAPRKG IYSFNFHVVK
     VYNRQTIQVS LMLNGWPVIS AFAGDQDVTR EAASNGVLIQ MEKGDRAYLK LERGNLMGGW
     KYSTFSGFLV FPL
 
 
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