KRIT1_DANRE
ID KRIT1_DANRE Reviewed; 740 AA.
AC F1REV3; B8JIZ5; Q0Z803;
DT 25-JAN-2012, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 73.
DE RecName: Full=Krev interaction trapped protein 1;
DE Short=Krev interaction trapped 1;
DE AltName: Full=Cerebral cavernous malformations 1 protein homolog;
DE AltName: Full=Santa;
GN Name=krit1; Synonyms=ccm1, san; ORFNames=zgc:63585;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=16873582; DOI=10.1242/dev.02469;
RA Mably J.D., Chuang L.P., Serluca F.C., Mohideen M.-A.P.K., Chen J.-N.,
RA Fishman M.C.;
RT "santa and valentine pattern concentric growth of cardiac myocardium in the
RT zebrafish.";
RL Development 133:3139-3146(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP INTERACTION WITH HEG1 AND CCM2.
RX PubMed=19151727; DOI=10.1038/nm.1918;
RA Kleaveland B., Zheng X., Liu J.J., Blum Y., Tung J.J., Zou Z.,
RA Sweeney S.M., Chen M., Guo L., Lu M.M., Zhou D., Kitajewski J.,
RA Affolter M., Ginsberg M.H., Kahn M.L.;
RT "Regulation of cardiovascular development and integrity by the heart of
RT glass-cerebral cavernous malformation protein pathway.";
RL Nat. Med. 15:169-176(2009).
RN [4]
RP FUNCTION, INTERACTION WITH RAP1, AND MUTAGENESIS OF ARG-449.
RX PubMed=21633110; DOI=10.1091/mbc.e11-02-0157;
RA Liu J.J., Stockton R.A., Gingras A.R., Ablooglu A.J., Han J., Bobkov A.A.,
RA Ginsberg M.H.;
RT "A mechanism of Rap1-induced stabilization of endothelial cell--cell
RT junctions.";
RL Mol. Biol. Cell 22:2509-2519(2011).
RN [5]
RP FUNCTION.
RX PubMed=23007647; DOI=10.1083/jcb.201205109;
RA Gingras A.R., Liu J.J., Ginsberg M.H.;
RT "Structural basis of the junctional anchorage of the cerebral cavernous
RT malformations complex.";
RL J. Cell Biol. 199:39-48(2012).
CC -!- FUNCTION: Component of the CCM signaling pathway which is a crucial
CC regulator of heart and vessel formation and integrity. Negative
CC regulator of angiogenesis. Inhibits endothelial proliferation,
CC apoptosis, migration, lumen formation and sprouting angiogenesis in
CC primary endothelial cells. Plays a role in integrin signaling. Plays an
CC important role in the maintenance of the intracellular reactive oxygen
CC species (ROS) homeostasis to prevent oxidative cellular damage.
CC Facilitates the down-regulation of cyclin-D1 (CCND1) levels required
CC for cell transition from proliferative growth to quiescence by
CC preventing the accumulation of intracellular ROS. Probable microtubule-
CC associated protein that may bind to phosphatidylinositol 4,5-
CC bisphosphate (PIP2)-containing membranes (By similarity). Required for
CC correct endothelial cell polarity and cell junction stabilization in
CC cardiovascular development. May play a role in the regulation of
CC macroautophagy through the down-regulation of the mTOR pathway (By
CC similarity). {ECO:0000250, ECO:0000250|UniProtKB:O00522,
CC ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:23007647}.
CC -!- SUBUNIT: Interacts with heg1 and ccm2; greatly facilitates ccm2-binding
CC to heg1. Interacts with rap1. {ECO:0000269|PubMed:19151727,
CC ECO:0000269|PubMed:21633110}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cell membrane;
CC Peripheral membrane protein. Cell junction. Note=KRIT1 and CDH5
CC reciprocally regulate their localization to endothelial cell-cell
CC junctions (By similarity). Association with RAP1 relocalizes KRIT1 from
CC microtubules to cell junction membranes. {ECO:0000250}.
CC -!- DEVELOPMENTAL STAGE: Expressed in the ventricular zone of the brain at
CC 28 hours post fertilization (hpf) and at lower levels, throughout the
CC entire brain and in the posterior cardinal vein. Venous expression is
CC maintained at 48 hpf. At the same time, there is also prominent
CC notochord expression. {ECO:0000269|PubMed:16873582}.
CC -!- DOMAIN: The FERM domain mediates binding to rap1.
CC -!- DOMAIN: The N-terminal domain has structural similarity to the nudix
CC hydrolase domain, despite the absence of a nudix box and low sequence
CC similarity with nudix hydrolase domains.
CC {ECO:0000250|UniProtKB:O00522}.
CC -!- DOMAIN: Contains 4 ANK repeats that precede the FERM domain.
CC {ECO:0000250|UniProtKB:O00522}.
CC -!- DISRUPTION PHENOTYPE: The heart chambers in mutant animals are huge,
CC constituted of a monolayered myocardium lined by endocardium.
CC {ECO:0000269|PubMed:16873582}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAX12105.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; DQ677877; ABG29498.1; -; mRNA.
DR EMBL; CR855331; CAX12105.1; ALT_INIT; Genomic_DNA.
DR AlphaFoldDB; F1REV3; -.
DR SMR; F1REV3; -.
DR STRING; 7955.ENSDARP00000110167; -.
DR PaxDb; F1REV3; -.
DR ZFIN; ZDB-GENE-030131-555; krit1.
DR eggNOG; KOG4335; Eukaryota.
DR InParanoid; F1REV3; -.
DR OMA; FAIWIAS; -.
DR PhylomeDB; F1REV3; -.
DR TreeFam; TF317921; -.
DR PRO; PR:F1REV3; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IMP:ZFIN.
DR GO; GO:0009948; P:anterior/posterior axis specification; IGI:ZFIN.
DR GO; GO:0003181; P:atrioventricular valve morphogenesis; IMP:ZFIN.
DR GO; GO:0001568; P:blood vessel development; IMP:ZFIN.
DR GO; GO:0072554; P:blood vessel lumenization; IMP:ZFIN.
DR GO; GO:0048514; P:blood vessel morphogenesis; IMP:ZFIN.
DR GO; GO:0045454; P:cell redox homeostasis; IBA:GO_Central.
DR GO; GO:0001886; P:endothelial cell morphogenesis; IMP:ZFIN.
DR GO; GO:0060047; P:heart contraction; IGI:ZFIN.
DR GO; GO:0007507; P:heart development; IMP:ZFIN.
DR GO; GO:0003007; P:heart morphogenesis; IMP:ZFIN.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IBA:GO_Central.
DR GO; GO:0045602; P:negative regulation of endothelial cell differentiation; IMP:ZFIN.
DR GO; GO:2000114; P:regulation of establishment of cell polarity; IBA:GO_Central.
DR GO; GO:0007033; P:vacuole organization; IMP:ZFIN.
DR GO; GO:0001570; P:vasculogenesis; IMP:ZFIN.
DR CDD; cd14473; FERM_B-lobe; 1.
DR CDD; cd13197; FERM_C_CCM1; 1.
DR Gene3D; 1.20.80.10; -; 1.
DR Gene3D; 1.25.40.20; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.70.2240; -; 1.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_sf.
DR InterPro; IPR035963; FERM_2.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR000299; FERM_domain.
DR InterPro; IPR041791; KRIT1_FERM_C.
DR InterPro; IPR032022; NUDIX.
DR InterPro; IPR043058; NUDIX_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR Pfam; PF13637; Ank_4; 1.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF16705; NUDIX_5; 1.
DR SMART; SM00248; ANK; 3.
DR SMART; SM00295; B41; 1.
DR SUPFAM; SSF47031; SSF47031; 1.
DR SUPFAM; SSF48403; SSF48403; 1.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 1.
DR PROSITE; PS50057; FERM_3; 1.
PE 1: Evidence at protein level;
KW Angiogenesis; ANK repeat; Cell junction; Cell membrane; Cytoplasm;
KW Cytoskeleton; Developmental protein; Membrane; Reference proteome; Repeat.
FT CHAIN 1..740
FT /note="Krev interaction trapped protein 1"
FT /id="PRO_0000415378"
FT REPEAT 284..313
FT /note="ANK 1"
FT /evidence="ECO:0000255"
FT REPEAT 317..347
FT /note="ANK 2"
FT /evidence="ECO:0000255"
FT REPEAT 351..381
FT /note="ANK 3"
FT /evidence="ECO:0000255"
FT REPEAT 385..416
FT /note="ANK 4"
FT /evidence="ECO:0000255"
FT DOMAIN 417..740
FT /note="FERM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00084"
FT REGION 1..168
FT /note="N-terminal domain similar to Nudix hydrolase domain"
FT /evidence="ECO:0000250"
FT MUTAGEN 449
FT /note="R->E: Dilated heart phenotype."
FT /evidence="ECO:0000269|PubMed:21633110"
FT CONFLICT 50
FT /note="K -> E (in Ref. 1; ABG29498)"
FT /evidence="ECO:0000305"
FT CONFLICT 69
FT /note="E -> G (in Ref. 1; ABG29498)"
FT /evidence="ECO:0000305"
FT CONFLICT 570
FT /note="Q -> R (in Ref. 1; ABG29498)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 740 AA; 84379 MW; 8E44AE3A68C24EB1 CRC64;
MGNQELEEVF VAVIRPKNTT SLNSKEYRAK SYEILLIEVP LEGKEKKRKK VLLGTKIHAD
SDRTKSILEF VDETTKPISN NQGIIGKRVV HMRKFLLDGD SGGKEASLFI VPINVKDNSK
SVHHPGSPSF YCLQDIMRVC SETSAHFSSS TSKMLLALDK WLAEQHTVPH AIPALFRPAP
VDRVKTNVSN PAYAVEKQTD GTLHMGYTAL EIKSKLMSLE KADLCIQNPL YGSDLQYTNR
VDKVIINPYF GLGAPDYSKI QIPKRDKWQH SMTSVTEDKE RQWVDDFPLH RSACEGDTEL
LSKLLDGGFS VKQLDSDHWA PIHYACWHGK VEATKLLLEK GNCNPNLLNG QLSSPLHFAA
IGGHAEIVQL LLQHPEIDRH IEDQQKRSPL QVCEENKQNN WEETVNLLQQ ASNKPYEKVR
IYRMDGSYRS VELKHGNNTT VQQIMEGMRL SQETQQYFTI WICSENLSLQ LKPYHKPLQH
LRMWSEIVTD LTALDPQRES PQLFLRRDVR LPLEVEKKVE DPLSILILFD EARHCLLKGF
LSTSDNKLIT LASLLLQIIY GNYDSKKHKQ GFLNEENLKS IVPISKVKSK AHHWTNRILH
EYKSLSTSEG VSKEMHHLQR LFLQNCWDIP TYGAAFFTGQ VFTKASSSTH KVIRVYVGVN
TKGLHLMNME TKVLHLSLEY GTFMWQLGQA DQYVQIHSLE NKKNFVVHTK QAGLIVKLLM
KLSGQIAPND RAVSDKYAYG
