EFC4B_MOUSE
ID EFC4B_MOUSE Reviewed; 726 AA.
AC Q3UP38; A0A1D5RLZ8; B9EKF2;
DT 03-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 07-APR-2021, sequence version 2.
DT 03-AUG-2022, entry version 114.
DE RecName: Full=EF-hand calcium-binding domain-containing protein 4B;
DE AltName: Full=Calcium release-activated channel regulator 2A;
DE AltName: Full=Ras-related protein Rab-46 {ECO:0000250|UniProtKB:Q9BSW2};
GN Name=Cracr2a;
GN Synonyms=Efcab4b, Gm1073, Rab46 {ECO:0000250|UniProtKB:Q9BSW2};
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Spleen;
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 [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [4]
RP ALTERNATIVE SPLICING (ISOFORM 2), FUNCTION (ISOFORM 2), AND TISSUE
RP SPECIFICITY (ISOFORM 2).
RX PubMed=27016526; DOI=10.1126/scisignal.aac9171;
RA Srikanth S., Kim K.D., Gao Y., Woo J.S., Ghosh S., Calmettes G., Paz A.,
RA Abramson J., Jiang M., Gwack Y.;
RT "A large Rab GTPase encoded by CRACR2A is a component of subsynaptic
RT vesicles that transmit T cell activation signals.";
RL Sci. Signal. 9:ra31-ra31(2016).
RN [5]
RP FUNCTION (ISOFORM 2), AND TISSUE SPECIFICITY (ISOFORMS 1 AND 2).
RX PubMed=29987160; DOI=10.4049/jimmunol.1800659;
RA Woo J.S., Srikanth S., Kim K.D., Elsaesser H., Lu J., Pellegrini M.,
RA Brooks D.G., Sun Z., Gwack Y.;
RT "CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17
RT Responses.";
RL J. Immunol. 201:1174-1185(2018).
CC -!- FUNCTION: [Isoform 1]: Ca(2+)-binding protein that plays a key role in
CC store-operated Ca(2+) entry (SOCE) in T-cells by regulating CRAC
CC channel activation. Acts as a cytoplasmic calcium-sensor that
CC facilitates the clustering of ORAI1 and STIM1 at the junctional regions
CC between the plasma membrane and the endoplasmic reticulum upon low
CC Ca(2+) concentration. It thereby regulates CRAC channel activation,
CC including translocation and clustering of ORAI1 and STIM1. Upon
CC increase of cytoplasmic Ca(2+) resulting from opening of CRAC channels,
CC dissociates from ORAI1 and STIM1, thereby destabilizing the ORAI1-STIM1
CC complex (By similarity). {ECO:0000250|UniProtKB:Q9BSW2}.
CC -!- FUNCTION: [Isoform 2]: Rab GTPase that mediates the trafficking of
CC Weibel-Palade bodies (WPBs) to microtubule organizing center (MTOC) in
CC endothelial cells in response to acute inflammatory stimuli (By
CC similarity). During histamine (but not thrombin) stimulation of
CC endothelial cells, the dynein-bound form induces retrograde transport
CC of a subset of WPBs along microtubules to the MTOC in a Ca(2+)-
CC independent manner and its GTPase activity is essential for this
CC function (By similarity). Ca(2+)-regulated dynein adapter protein that
CC activates dynein-mediated transport and dynein-dynactin motility on
CC microtubules and regulates endosomal trafficking of CD47 (By
CC similarity). Acts as an intracellular signaling module bridging two
CC important T-cell receptor (TCR) signaling pathways, Ca(2+)-NFAT and
CC JNK, to affect T-cell activation (PubMed:27016526). In resting T-cells,
CC is predominantly localized near TGN network in a GTP-bound form, upon
CC TCR stimulation, localizes at the immunological synapse via interaction
CC with VAV1 to activate downstream Ca(2+)-NFAT and JNK signaling pathways
CC (By similarity). Plays a role in T-helper 1 (Th1) cell differentiation
CC and T-helper 17 (Th17) cell effector function (PubMed:29987160). Plays
CC a role in store-operated Ca(2+) entry (SOCE) in T-cells by regulating
CC CRAC channel activation (By similarity). {ECO:0000250|UniProtKB:Q9BSW2,
CC ECO:0000269|PubMed:27016526, ECO:0000269|PubMed:29987160}.
CC -!- SUBUNIT: [Isoform 1]: Interacts with ORAI1 and STIM1; the interaction
CC is direct and takes place in absence of Ca(2+). Forms a complex with
CC ORAI1 and STIM1 at low concentration of Ca(2+), the complex dissociates
CC at elevated Ca(2+) concentrations. Interacts with ORAI2 and ORAI3.
CC {ECO:0000250|UniProtKB:Q9BSW2}.
CC -!- SUBUNIT: [Isoform 2]: Interacts with DYNC1H1 and VAV1 (By similarity).
CC Interacts with the dynein-dynactin complex in a Ca(2+)-dependent manner
CC (By similarity). {ECO:0000250|UniProtKB:Q9BSW2}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q9BSW2}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q9BSW2}. Cytoplasm, cytoskeleton, microtubule
CC organizing center {ECO:0000250|UniProtKB:Q9BSW2}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9BSW2}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q9BSW2}. Golgi apparatus, trans-Golgi network
CC membrane {ECO:0000250|UniProtKB:Q9BSW2}. Vesicle
CC {ECO:0000250|UniProtKB:Q9BSW2}. Note=T-cell activation-induced
CC elevation of intracellular of Ca(2+) stimulates its transport toward
CC the microtubule organizing center (MTOC). Histamine stimulation induces
CC a trafficking to the MTOC in a GTP-binding-dependent but Ca(2+)-
CC binding-independent manner. Localizes to Golgi membrane in resting T-
CC cells and upon its interaction with VAV1, is translocated from the
CC Golgi membrane to the immunological synapse via subsynaptic vesicles.
CC Its localization in the Golgi membrane requires isoprenylation and GTP-
CC binding. {ECO:0000250|UniProtKB:Q9BSW2}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2; Synonyms=CRACR2A-A {ECO:0000303|PubMed:27016526};
CC IsoId=Q3UP38-2; Sequence=Displayed;
CC Name=1;
CC IsoId=Q3UP38-1; Sequence=VSP_060979, VSP_060980;
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Abundantly expressed in T helper 1 and
CC T helper 17 cells. {ECO:0000269|PubMed:29987160}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in lymphoid organs including
CC spleen and lymph nodes (PubMed:27016526). Abundantly expressed in T
CC helper 1 and T helper 17 cells (PubMed:29987160).
CC {ECO:0000269|PubMed:27016526, ECO:0000269|PubMed:29987160}.
CC -!- SIMILARITY: Belongs to the EFCAB4 family. {ECO:0000305}.
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DR EMBL; AK143832; BAE25559.1; -; mRNA.
DR EMBL; GL456132; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC150869; AAI50870.1; -; mRNA.
DR CCDS; CCDS20566.1; -. [Q3UP38-1]
DR CCDS; CCDS90125.1; -. [Q3UP38-2]
DR RefSeq; NP_001028636.1; NM_001033464.3. [Q3UP38-1]
DR RefSeq; XP_006506407.1; XM_006506344.2.
DR AlphaFoldDB; Q3UP38; -.
DR SMR; Q3UP38; -.
DR STRING; 10090.ENSMUSP00000071494; -.
DR iPTMnet; Q3UP38; -.
DR PhosphoSitePlus; Q3UP38; -.
DR MaxQB; Q3UP38; -.
DR PaxDb; Q3UP38; -.
DR PRIDE; Q3UP38; -.
DR ProteomicsDB; 277693; -. [Q3UP38-1]
DR ProteomicsDB; 349357; -.
DR Antibodypedia; 22229; 186 antibodies from 30 providers.
DR Ensembl; ENSMUST00000071563; ENSMUSP00000071494; ENSMUSG00000061414. [Q3UP38-1]
DR Ensembl; ENSMUST00000212051; ENSMUSP00000148569; ENSMUSG00000061414. [Q3UP38-2]
DR GeneID; 381812; -.
DR KEGG; mmu:381812; -.
DR UCSC; uc009dwa.1; mouse. [Q3UP38-2]
DR CTD; 84766; -.
DR MGI; MGI:2685919; Cracr2a.
DR VEuPathDB; HostDB:ENSMUSG00000061414; -.
DR eggNOG; KOG0078; Eukaryota.
DR GeneTree; ENSGT00440000033504; -.
DR InParanoid; Q3UP38; -.
DR OMA; CEARFSP; -.
DR OrthoDB; 1184845at2759; -.
DR PhylomeDB; Q3UP38; -.
DR TreeFam; TF329556; -.
DR BioGRID-ORCS; 381812; 2 hits in 71 CRISPR screens.
DR ChiTaRS; Cracr2a; mouse.
DR PRO; PR:Q3UP38; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q3UP38; protein.
DR Bgee; ENSMUSG00000061414; Expressed in granulocyte and 45 other tissues.
DR ExpressionAtlas; Q3UP38; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; ISS:UniProtKB.
DR GO; GO:0001772; C:immunological synapse; ISS:UniProtKB.
DR GO; GO:0005815; C:microtubule organizing center; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0032588; C:trans-Golgi network membrane; ISS:UniProtKB.
DR GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR GO; GO:0033093; C:Weibel-Palade body; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; ISS:UniProtKB.
DR GO; GO:0032237; P:activation of store-operated calcium channel activity; ISS:UniProtKB.
DR GO; GO:0016197; P:endosomal transport; ISS:UniProtKB.
DR GO; GO:0051928; P:positive regulation of calcium ion transport; ISS:UniProtKB.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0034776; P:response to histamine; ISS:UniProtKB.
DR GO; GO:0002115; P:store-operated calcium entry; ISS:UniProtKB.
DR GO; GO:0045063; P:T-helper 1 cell differentiation; IMP:UniProtKB.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR Pfam; PF13499; EF-hand_7; 1.
DR Pfam; PF00071; Ras; 1.
DR SMART; SM00054; EFh; 2.
DR SMART; SM00174; RHO; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 1.
PE 2: Evidence at transcript level;
KW Adaptive immunity; Alternative splicing; Calcium; Calcium transport;
KW Cell membrane; Coiled coil; Cytoplasm; Cytoskeleton; Golgi apparatus;
KW GTP-binding; Immunity; Ion transport; Lipoprotein; Membrane; Metal-binding;
KW Nucleotide-binding; Prenylation; Reference proteome; Repeat; Transport.
FT CHAIN 1..726
FT /note="EF-hand calcium-binding domain-containing protein
FT 4B"
FT /id="PRO_0000283047"
FT DOMAIN 78..113
FT /note="EF-hand"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT REGION 1..30
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 343..535
FT /note="Proline-rich domain (PRD) which mediates interaction
FT with VAV1"
FT /evidence="ECO:0000250|UniProtKB:Q9BSW2"
FT COILED 202..376
FT /evidence="ECO:0000255"
FT COMPBIAS 1..19
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 93
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 95
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 102
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT BINDING 547..554
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P63000"
FT BINDING 595..599
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P63000"
FT BINDING 654..657
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:P63000"
FT LIPID 724
FT /note="S-geranylgeranyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9BSW2"
FT VAR_SEQ 281..310
FT /note="LEGQCAALHNDKHETKAENSKLRLTNQELA -> VGYCGDIVGPQLFQLSLP
FT LPHALHHSSMDF (in isoform 1)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_060979"
FT VAR_SEQ 311..726
FT /note="Missing (in isoform 1)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_060980"
FT CONFLICT 272
FT /note="E -> G (in Ref. 3; AAI50870)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 726 AA; 82667 MW; 934820B3E70D7133 CRC64;
MATPSGREDS SSQTPGHGKQ GSGACVEQLD HPEKLEVEMP DQSAMWKKAQ EFFQTCDSEG
KGFIARTDMQ RLHQELPLSL EELEDVFDAL DADGNGFLTP EEFTTGFSHF FFSQNIQGEE
EADQQVAQLQ EEKVYQSRGE EDVGDMDHDE EAQFQMLMDR LGAQKVLEDE SDVRQLWLQL
RKDEPHLLSN FEDLLTTIFA QLQEAHEQKN ELECALRKKI AAYDEEIQHL YEEMEQQIKS
EREQFLLKDT ERFQARSREL EKKLSAKEQE LERLNQKQRK LEGQCAALHN DKHETKAENS
KLRLTNQELA RELERTSHQL QEAQQQLESL QREACELQQE KEMEVYRVTE SLQREKSGLL
KQLDFLRERN KHLRDERDIT FQKDKAAKAN TAASKASRKQ RSGSVIGKYV DGRGILRSQS
EEEEDVFSAP RRRSSVGLSA YLQAEEDLGT GEPGSGVPRR QALRRIISIE EDPLPQLLEG
GFEKPLSRCP EEEEVSDQGT ERQSVAAPVL DLIPTSPRGQ PVGKETLYKE ERVPSTPDRL
FKIVFVGDSA VGKTSFLRRL CEARFSPGMA ATVGIDYRVK TVTVDNAQVA LQLWDTAGQE
RYRCISQQFF RKADGVAVMY DLTAKQSFLS IRQWLSSVEE AVGDRIPVLL LGNKLDNEKE
REVPRGLGEQ LAKENNLIFY ECSACSGHNA QESLLHLARL LKEQEDTVRN DTIQVGPPAK
KKSCCG
