UN13D_MOUSE
ID UN13D_MOUSE Reviewed; 1085 AA.
AC B2RUP2; A2A856; A3R4M4; A3R4M5; Q571J0;
DT 01-SEP-2009, integrated into UniProtKB/Swiss-Prot.
DT 01-SEP-2009, sequence version 2.
DT 03-AUG-2022, entry version 101.
DE RecName: Full=Protein unc-13 homolog D;
DE AltName: Full=Munc13-4;
GN Name=Unc13d;
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] (ISOFORM 1), NUCLEOTIDE SEQUENCE [GENOMIC DNA]
RP OF 792-814, AND DISRUPTION PHENOTYPE.
RC STRAIN=C57BL/6J;
RX PubMed=17420270; DOI=10.1084/jem.20062447;
RA Crozat K., Hoebe K., Ugolini S., Hong N.A., Janssen E., Rutschmann S.,
RA Mudd S., Sovath S., Vivier E., Beutler B.;
RT "Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a
RT mouse model of type 3 familial hemophagocytic lymphohistiocytosis.";
RL J. Exp. Med. 204:853-863(2007).
RN [2]
RP ERRATUM OF PUBMED:17420270.
RA Crozat K., Hoebe K., Ugolini S., Hong N.A., Janssen E., Rutschmann S.,
RA Mudd S., Sovath S., Vivier E., Beutler B.;
RL J. Exp. Med. 205:737-737(2008).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 193-1085 (ISOFORM 2).
RC TISSUE=Spleen;
RA Okazaki N., Kikuno R.F., Ohara R., Inamoto S., Nagase T., Ohara O.,
RA Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene. The
RT complete nucleotide sequences of mouse KIAA-homologous cDNAs identified by
RT screening of terminal sequences of cDNA clones randomly sampled from size-
RT fractionated libraries.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-149, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [7]
RP FUNCTION, INTERACTION WITH RAB27A AND DOC2A, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=18354201; DOI=10.4049/jimmunol.180.7.4774;
RA Higashio H., Nishimura N., Ishizaki H., Miyoshi J., Orita S., Sakane A.,
RA Sasaki T.;
RT "Doc2 alpha and Munc13-4 regulate Ca(2+) -dependent secretory lysosome
RT exocytosis in mast cells.";
RL J. Immunol. 180:4774-4784(2008).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-149, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Lung, Pancreas, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Plays a role in cytotoxic granule exocytosis in lymphocytes.
CC Required for both granule maturation and granule docking and priming at
CC the immunologic synapse. Regulates assembly of recycling and late
CC endosomal structures, leading to the formation of an endosomal exocytic
CC compartment that fuses with perforin-containing granules at the
CC immunologic synapse and licences them for exocytosis (By similarity).
CC Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells.
CC {ECO:0000250, ECO:0000269|PubMed:18354201}.
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00041};
CC -!- SUBUNIT: Interacts with RAB27A and DOC2A. Both RAB27A and DOC2A can
CC simultaneously bind UNC13D. {ECO:0000269|PubMed:18354201}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000250};
CC Peripheral membrane protein {ECO:0000250}. Late endosome {ECO:0000250}.
CC Recycling endosome {ECO:0000250}. Lysosome
CC {ECO:0000269|PubMed:18354201}. Note=Colocalizes with cytotoxic granules
CC at the plasma membrane. Localizes to endosomal exocytic vesicles.
CC {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=B2RUP2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=B2RUP2-2; Sequence=VSP_037950;
CC -!- TISSUE SPECIFICITY: Mast cells. {ECO:0000269|PubMed:18354201}.
CC -!- DOMAIN: The MHD1 and MHD2 domains mediate localization on recycling
CC endosomes and lysosome. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: A truncating mutation is the cause of the jinxed
CC phenotype (jinx), a chemically-induced mutation that make mice
CC susceptible to murine cytomegalovirus (MCMV). It is a mouse model of
CC human type 3 familial hemophagocytic lymphohistiocytosis. Affected mice
CC produce a truncated protein that lack the second of the C2 domains and
CC part of the second MHD domain. In jinx homozygotes, activated NK cells
CC and cytotoxic T-lymphocytes (CTLs) fail to degranulate, although they
CC retain the ability to produce cytokines. Mice do not spontaneously
CC develop clinical features of hemophagocytic lymphohistiocytosis (HLH),
CC but do so when infected with lymphocytic choriomeningitis virus (LCMV),
CC exhibiting hyperactivation of CTLs and antigen-presenting cells, and
CC inadequate restriction of viral proliferation. In contrast, neither
CC Listeria monocytogenes nor MCMV induce the syndrome.
CC {ECO:0000269|PubMed:17420270}.
CC -!- SIMILARITY: Belongs to the unc-13 family. {ECO:0000305}.
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DR EMBL; EF127645; ABO15439.1; -; mRNA.
DR EMBL; EF127646; ABO15440.1; -; Genomic_DNA.
DR EMBL; AL607108; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC141289; AAI41290.1; -; mRNA.
DR EMBL; AK220199; BAD90124.1; -; mRNA.
DR CCDS; CCDS25656.1; -. [B2RUP2-2]
DR RefSeq; NP_001009573.2; NM_001009573.2. [B2RUP2-2]
DR RefSeq; XP_006534251.1; XM_006534188.2. [B2RUP2-1]
DR RefSeq; XP_006534252.1; XM_006534189.2. [B2RUP2-1]
DR RefSeq; XP_006534253.1; XM_006534190.2. [B2RUP2-1]
DR RefSeq; XP_011247556.1; XM_011249254.2.
DR AlphaFoldDB; B2RUP2; -.
DR SMR; B2RUP2; -.
DR CORUM; B2RUP2; -.
DR STRING; 10090.ENSMUSP00000102058; -.
DR iPTMnet; B2RUP2; -.
DR PhosphoSitePlus; B2RUP2; -.
DR EPD; B2RUP2; -.
DR jPOST; B2RUP2; -.
DR MaxQB; B2RUP2; -.
DR PaxDb; B2RUP2; -.
DR PRIDE; B2RUP2; -.
DR ProteomicsDB; 298197; -. [B2RUP2-1]
DR ProteomicsDB; 298198; -. [B2RUP2-2]
DR Antibodypedia; 32273; 230 antibodies from 36 providers.
DR DNASU; 70450; -.
DR Ensembl; ENSMUST00000075036; ENSMUSP00000074549; ENSMUSG00000057948. [B2RUP2-2]
DR Ensembl; ENSMUST00000106450; ENSMUSP00000102058; ENSMUSG00000057948. [B2RUP2-1]
DR Ensembl; ENSMUST00000106451; ENSMUSP00000102059; ENSMUSG00000057948. [B2RUP2-1]
DR Ensembl; ENSMUST00000174822; ENSMUSP00000134260; ENSMUSG00000057948. [B2RUP2-2]
DR GeneID; 70450; -.
DR KEGG; mmu:70450; -.
DR UCSC; uc007mjt.1; mouse. [B2RUP2-2]
DR CTD; 201294; -.
DR MGI; MGI:1917700; Unc13d.
DR VEuPathDB; HostDB:ENSMUSG00000057948; -.
DR eggNOG; KOG1328; Eukaryota.
DR GeneTree; ENSGT00730000110939; -.
DR HOGENOM; CLU_003295_1_0_1; -.
DR InParanoid; B2RUP2; -.
DR OMA; ICKTKAF; -.
DR OrthoDB; 72416at2759; -.
DR PhylomeDB; B2RUP2; -.
DR TreeFam; TF315526; -.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR BioGRID-ORCS; 70450; 4 hits in 72 CRISPR screens.
DR ChiTaRS; Unc13d; mouse.
DR PRO; PR:B2RUP2; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; B2RUP2; protein.
DR Bgee; ENSMUSG00000057948; Expressed in granulocyte and 90 other tissues.
DR ExpressionAtlas; B2RUP2; baseline and differential.
DR Genevisible; B2RUP2; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0070382; C:exocytic vesicle; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005770; C:late endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; ISO:MGI.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0055037; C:recycling endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0099503; C:secretory vesicle; IBA:GO_Central.
DR GO; GO:0033093; C:Weibel-Palade body; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031267; F:small GTPase binding; ISO:MGI.
DR GO; GO:0051607; P:defense response to virus; IMP:MGI.
DR GO; GO:0061789; P:dense core granule priming; ISO:MGI.
DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI.
DR GO; GO:0002467; P:germinal center formation; IMP:MGI.
DR GO; GO:0002432; P:granuloma formation; IMP:MGI.
DR GO; GO:0043320; P:natural killer cell degranulation; IMP:MGI.
DR GO; GO:0006909; P:phagocytosis; IMP:MGI.
DR GO; GO:0045921; P:positive regulation of exocytosis; ISO:MGI.
DR GO; GO:1903307; P:positive regulation of regulated secretory pathway; ISO:MGI.
DR GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; IMP:UniProtKB.
DR GO; GO:0043304; P:regulation of mast cell degranulation; ISO:MGI.
DR GO; GO:0046903; P:secretion; IBA:GO_Central.
DR Gene3D; 2.60.40.150; -; 2.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR010439; MUN_dom.
DR InterPro; IPR014770; Munc13_1.
DR InterPro; IPR014772; Munc13_dom-2.
DR Pfam; PF00168; C2; 2.
DR Pfam; PF06292; MUN; 1.
DR SMART; SM00239; C2; 2.
DR SUPFAM; SSF49562; SSF49562; 2.
DR PROSITE; PS50004; C2; 2.
DR PROSITE; PS51258; MHD1; 1.
DR PROSITE; PS51259; MHD2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Cytoplasm; Endosome; Exocytosis; Lysosome;
KW Membrane; Metal-binding; Phosphoprotein; Reference proteome; Repeat.
FT CHAIN 1..1085
FT /note="Protein unc-13 homolog D"
FT /id="PRO_0000382950"
FT DOMAIN 91..238
FT /note="C2 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 554..674
FT /note="MHD1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00587"
FT DOMAIN 785..892
FT /note="MHD2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00588"
FT DOMAIN 909..1034
FT /note="C2 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT REGION 24..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 239..542
FT /note="Interaction with RAB27A"
FT /evidence="ECO:0000250"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 205
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 207
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 939
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 940
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 940
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 946
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 1004
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 1004
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 1006
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 1006
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT BINDING 1012
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT MOD_RES 149
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT VAR_SEQ 480..481
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.5"
FT /id="VSP_037950"
FT CONFLICT 792
FT /note="P -> F (in Ref. 1; ABO15440)"
FT /evidence="ECO:0000305"
FT CONFLICT 796
FT /note="F -> N (in Ref. 1; ABO15440)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1085 AA; 123119 MW; BA46A15BBF62B8B7 CRC64;
MATHLSHPQR RPLLRQAIKI RRRRVRDLQD PPPQATQEVQ VQSHHFSPEE RDLLYEEALY
TVLHRLGQPE PNHVKEASEL LSYLQEAFQV QPEEHQQMLR RVRELEKPVF CLKATVKQAK
GILGKDVSGF SDPYCLLGIE QKVGVAEGSP VSRRRQKAVV KHTIPEEETH RTQVKSQTLN
PVWDETFILE FEDIANASFH LDMWDLDTVE SVRQKLGELT DLHGLRRIFK EARKDKGQDD
FLGNVVLRLQ DLRCREDQWF PLEPCTETYP DRGQCHLQFQ FIHKRRATAA SRSQPSYTVH
FHLLQQLVSH EVTQHQAGST SWDASLSPQA VTILFLHATQ KDLSDFHQSM AQWLAYSRLY
QSLEFPSSCL LHPITSIEYQ WIQGRLKAEQ REELATSFTS LLAYGLSLIR KFRSVFPLSV
SDSPSRLQSL LRVLVQMCKM KAFGELCPDS APLSQLVSEA LRMGTVEWFH LMQQHHQPMV
QGILEAGKAL LNLVQDVMGD LYQCRRTWNK IFHNVLKIDL FSMAFLELQW LVAKRVQDHT
VAAGNLVSPD IGESLFQLYV SLKELCQLGP VPSDSREVLA LDGFHRWFQP AIPSWLQKTY
SVALERVQRA VQMDTLVPLG ELTKHSTSAV DLSTCFAQIS HTARQLDWPD PEEAFMITVK
FVEDTCRLAL VYCSLIKARA RELSAVQKDQ SQAADMLCVV VNNMEQLRLI IDKLPTQLAW
EALEQRVGAV LEEGQLQNTL HAQLQGALAG LGHEIRTGVR TLAEQLEVGI ATHIQKLIGV
KESVLPEDAI LPLMKFLEVK LCYMNTNLVQ ENFSSLLTLL WTHTLTVLVE VASSQRSSSL
ASGRLKVALQ NLEVCFHAEG CGLPPEALHT DTFQALQNDL ELQAASSREL IQKYFCSRIQ
QQAETTSERL GAVTVKVSYR ASEQRLRVEL LSASSLLPLD SNGSSDPFVQ LTLEPRHEFP
EVAPRETQKH KKELHPLFDE TFEFLVPAEP CQKAWACLLL TVLDHDRLGA DDLEGEAFLP
LCRVPGLTDC AEPGEAPQMR LPLTYPAPNG DPILRLLESR KGDREAQAFV KLRRQRAKQA
SQHAP