KRIT1_HUMAN
ID KRIT1_HUMAN Reviewed; 736 AA.
AC O00522; A6NNU0; O43894; Q506L6; Q6U276; Q75N19; Q9H180; Q9H264; Q9HAX5;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2005, sequence version 2.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Krev interaction trapped protein 1;
DE Short=Krev interaction trapped 1;
DE AltName: Full=Cerebral cavernous malformations 1 protein;
GN Name=KRIT1; Synonyms=CCM1;
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 [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2),
RP TISSUE SPECIFICITY, AND INTERACTION WITH RAP1A.
RC TISSUE=Kidney, and Mammary cancer;
RX PubMed=9285558; DOI=10.1038/sj.onc.1201268;
RA Serebriiskii I., Estojak J., Sonoda G., Testa J.R., Golemis E.A.;
RT "Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing
RT protein encoded by a gene mapping to 7q21-22.";
RL Oncogene 15:1043-1049(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11161791; DOI=10.1006/geno.2000.6410;
RA Zhang J., Clatterbuck R.E., Rigamonti D., Dietz H.C.;
RT "Cloning of the murine Krit1 cDNA reveals novel mammalian 5' coding
RT exons.";
RL Genomics 70:392-395(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND ALTERNATIVE SPLICING.
RX PubMed=11161805; DOI=10.1006/geno.2000.6426;
RA Sahoo T., Goenaga-Diaz E., Serebriiskii I.G., Thomas J.W., Kotova E.,
RA Cuellar J.G., Peloquin J.M., Golemis E., Beitinjaneh F., Green E.D.,
RA Johnson E.W., Marchuk D.A.;
RT "Computational and experimental analyses reveal previously undetected
RT coding exons of the KRIT1 (CCM1) gene.";
RL Genomics 71:123-126(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ALTERNATIVE SPLICING, AND VARIANTS
RP CCM1 SER-97 AND GLU-569.
RX PubMed=12172908; DOI=10.1007/s00401-002-0552-6;
RA Kehrer-Sawatzki H., Wilda M., Braun V.M., Richter H.-P., Hameister H.;
RT "Mutation and expression analysis of the KRIT1 gene associated with
RT cerebral cavernous malformations (CCM1).";
RL Acta Neuropathol. 104:231-240(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Ferrera L., Marini V., Dorcaratto A., Pigatto F., Alberti F., Forni M.,
RA Cama A., Viale G., Origone P., Mareni C., Garre' C.;
RT "Four novel and three known KRIT1 mutations in CCM Italian patients:
RT Characterization at mRNA and protein level.";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Uterus;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-243, AND ALTERNATIVE SPLICING.
RX PubMed=11342228; DOI=10.1016/s0167-4781(00)00303-1;
RA Eerola I., McIntyre B., Vikkula M.;
RT "Identification of eight novel 5`-exons in cerebral capillary malformation
RT gene-1 (CCM1) encoding KRIT1.";
RL Biochim. Biophys. Acta 1517:464-467(2001).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 244-281.
RA Marini V., Ferrera L., Dorcaratto A., Forni M., Capra V., Origone P.,
RA Mareni C., Garre' C.;
RT "Six novel and three known KRIT1 mutations in CCM patients:
RT characterization at mRNA level.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP FUNCTION, INTERACTION WITH ITGB1 AND ITGB1BP1, AND MUTAGENESIS OF ASN-192
RP AND TYR-195.
RX PubMed=11741838; DOI=10.1093/hmg/10.25.2953;
RA Zhang J., Clatterbuck R.E., Rigamonti D., Chang D.D., Dietz H.C.;
RT "Interaction between krit1 and icap1alpha infers perturbation of integrin
RT beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous
RT malformation.";
RL Hum. Mol. Genet. 10:2953-2960(2001).
RN [12]
RP INTERACTION WITH ITGB1BP1, AND MUTAGENESIS OF ASN-192 AND TYR-195.
RX PubMed=11854171; DOI=10.1093/hmg/11.4.389;
RA Zawistowski J.S., Serebriiskii I.G., Lee M.F., Golemis E.A., Marchuk D.A.;
RT "KRIT1 association with the integrin-binding protein ICAP-1: a new
RT direction in the elucidation of cerebral cavernous malformations (CCM1)
RT pathogenesis.";
RL Hum. Mol. Genet. 11:389-396(2002).
RN [13]
RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH ITGB1BP1 AND RAP1A, INTERACTION
RP WITH ITGB1BP1 AND RAP1A, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 47-LYS--LYS-50 AND 192-ASN--TYR-195.
RX PubMed=17916086; DOI=10.1111/j.1742-4658.2007.06068.x;
RA Beraud-Dufour S., Gautier R., Albiges-Rizo C., Chardin P., Faurobert E.;
RT "Krit 1 interactions with microtubules and membranes are regulated by Rap1
RT and integrin cytoplasmic domain associated protein-1.";
RL FEBS J. 274:5518-5532(2007).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CDH5.
RX PubMed=20332120; DOI=10.1242/jcs.059329;
RA Lampugnani M.G., Orsenigo F., Rudini N., Maddaluno L., Boulday G.,
RA Chapon F., Dejana E.;
RT "CCM1 regulates vascular-lumen organization by inducing endothelial
RT polarity.";
RL J. Cell Sci. 123:1073-1080(2010).
RN [15]
RP FUNCTION.
RX PubMed=20668652; DOI=10.1371/journal.pone.0011786;
RA Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P.,
RA Retta S.F.;
RT "KRIT1 regulates the homeostasis of intracellular reactive oxygen
RT species.";
RL PLoS ONE 5:E11786-E11786(2010).
RN [16]
RP FUNCTION.
RX PubMed=20616044; DOI=10.1073/pnas.1000132107;
RA Wuestehube J., Bartol A., Liebler S.S., Bruetsch R., Zhu Y., Felbor U.,
RA Sure U., Augustin H.G., Fischer A.;
RT "Cerebral cavernous malformation protein CCM1 inhibits sprouting
RT angiogenesis by activating DELTA-NOTCH signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:12640-12645(2010).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RAP1A, AND MUTAGENESIS OF
RP ARG-452.
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 [18]
RP FUNCTION.
RX PubMed=26417067; DOI=10.15252/emmm.201505316;
RA Marchi S., Corricelli M., Trapani E., Bravi L., Pittaro A.,
RA Delle Monache S., Ferroni L., Patergnani S., Missiroli S., Goitre L.,
RA Trabalzini L., Rimessi A., Giorgi C., Zavan B., Cassoni P., Dejana E.,
RA Retta S.F., Pinton P.;
RT "Defective autophagy is a key feature of cerebral cavernous
RT malformations.";
RL EMBO Mol. Med. 7:1403-1417(2015).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 420-736 IN COMPLEX WITH RAP1B,
RP MUTAGENESIS OF SER-430; ARG-432 AND ARG-452, AND INTERACTION WITH RAP1B.
RX PubMed=22577140; DOI=10.1074/jbc.m112.361295;
RA Li X., Zhang R., Draheim K.M., Liu W., Calderwood D.A., Boggon T.J.;
RT "Structural basis for small G protein effector interaction of Ras-related
RT protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1).";
RL J. Biol. Chem. 287:22317-22327(2012).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 417-736 IN COMPLEX WITH HEG1,
RP INTERACTION WITH HEG1; RAP1A AND CCM2, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF LEU-717 AND LEU-721.
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).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.54 ANGSTROMS) OF 1-198 IN COMPLEX WITH ITGB1BP1,
RP INTERACTION WITH ITGB1BP1, FUNCTION, DOMAIN, AND MUTAGENESIS OF ALA-176;
RP ARG-179; PRO-182; ARG-185; ASN-192 AND TYR-195.
RX PubMed=23317506; DOI=10.1016/j.molcel.2012.12.005;
RA Liu W., Draheim K.M., Zhang R., Calderwood D.A., Boggon T.J.;
RT "Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin
RT activation.";
RL Mol. Cell 49:719-729(2013).
RN [22] {ECO:0007744|PDB:5D68}
RP X-RAY CRYSTALLOGRAPHY (2.91 ANGSTROMS) OF 259-736, AND ANK REPEAT DOMAIN.
RX PubMed=26458359; DOI=10.1016/j.jsb.2015.10.006;
RA Zhang R., Li X., Boggon T.J.;
RT "Structural analysis of the KRIT1 ankyrin repeat and FERM domains reveals a
RT conformationally stable ARD-FERM interface.";
RL J. Struct. Biol. 192:449-456(2015).
CC -!- FUNCTION: Component of the CCM signaling pathway which is a crucial
CC regulator of heart and vessel formation and integrity (By similarity).
CC Negative regulator of angiogenesis. Inhibits endothelial proliferation,
CC apoptosis, migration, lumen formation and sprouting angiogenesis in
CC primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-
CC dependent and independent manner, and inhibits ERK1/2 phosphorylation
CC indirectly through activation of the DELTA-NOTCH cascade. Acts in
CC concert with CDH5 to establish and maintain correct endothelial cell
CC polarity and vascular lumen and these effects are mediated by
CC recruitment and activation of the Par polarity complex and RAP1B.
CC Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and
CC RAP1B to the cell junction, and cell junction stabilization. Plays a
CC role in integrin signaling via its interaction with ITGB1BP1; this
CC prevents the interaction between ITGB1 and ITGB1BP1. Microtubule-
CC associated protein that binds to phosphatidylinositol 4,5-bisphosphate
CC (PIP2)-containing membranes in a GTP-bound RAP1-dependent manner. Plays
CC an important role in the maintenance of the intracellular reactive
CC oxygen species (ROS) homeostasis to prevent oxidative cellular damage.
CC Regulates the homeostasis of intracellular ROS through an antioxidant
CC pathway involving FOXO1 and SOD2. Facilitates the down-regulation of
CC cyclin-D1 (CCND1) levels required for cell transition from
CC proliferative growth to quiescence by preventing the accumulation of
CC intracellular ROS through the modulation of FOXO1 and SOD2 levels. May
CC play a role in the regulation of macroautophagy through the down-
CC regulation of the mTOR pathway (PubMed:26417067).
CC {ECO:0000250|UniProtKB:Q6S5J6, ECO:0000269|PubMed:11741838,
CC ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:20332120,
CC ECO:0000269|PubMed:20616044, ECO:0000269|PubMed:20668652,
CC ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:23317506,
CC ECO:0000269|PubMed:26417067}.
CC -!- SUBUNIT: Interacts with CDH5 (PubMed:20332120). Found in a complex, at
CC least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (via C-terminus
CC FERM domain) with RAP1A (active GTP-bound form preferentially); the
CC interaction does not induce the opening conformation of KRIT1.
CC Interacts (via FERM domain) with RAP1B. Interacts (via N-terminus NPXY
CC motif) with ITGB1BP1; the interaction induces the opening conformation
CC of KRIT1 and competes with ITGB1 for ITGB1BP1 interaction. Interacts
CC with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1.
CC Associates (via N-terminus and C-terminus regions) with microtubules;
CC the interaction is inhibited in presence of ITGB1BP1 and active GTP-
CC bound RAP1A. {ECO:0000269|PubMed:11741838, ECO:0000269|PubMed:11854171,
CC ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:20332120,
CC ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:22577140,
CC ECO:0000269|PubMed:23007647, ECO:0000269|PubMed:23317506,
CC ECO:0000269|PubMed:9285558}.
CC -!- INTERACTION:
CC O00522; Q9BSQ5: CCM2; NbExp=15; IntAct=EBI-1573121, EBI-1573056;
CC O00522; Q9BSQ5-1: CCM2; NbExp=2; IntAct=EBI-1573121, EBI-16157769;
CC O00522; Q9ULI3: HEG1; NbExp=5; IntAct=EBI-1573121, EBI-12734419;
CC O00522; O14713: ITGB1BP1; NbExp=4; IntAct=EBI-1573121, EBI-2127319;
CC O00522; P61086: UBE2K; NbExp=3; IntAct=EBI-1573121, EBI-473850;
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. Association with RAP1 relocalizes KRIT1 from microtubules to
CC cell junction membranes. Translocates from the cytoplasm along
CC microtubules to the cell membrane in a ITGB1BP1-dependent manner.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O00522-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O00522-2; Sequence=VSP_015800;
CC Name=3;
CC IsoId=O00522-3; Sequence=VSP_043327;
CC -!- TISSUE SPECIFICITY: Low levels in brain. Very weak expression found in
CC heart and muscle. {ECO:0000269|PubMed:9285558}.
CC -!- DOMAIN: The FERM domain mediates binding to RAP1A and RAP1B and is
CC necessary for binding to phosphatidylinositol 4,5-bisphosphate (PIP2).
CC {ECO:0000269|PubMed:23317506}.
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. The N-terminus and the C-
CC terminus part associate together via the NPAY binding motif and adopt a
CC lose conformation that is disrupted by ITGB1BP1, but not by RAP1A.
CC {ECO:0000269|PubMed:23317506}.
CC -!- DOMAIN: Contains 4 ANK repeats that precede the FERM domain.
CC {ECO:0000269|PubMed:26458359}.
CC -!- DISEASE: Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A form
CC of cerebral cavernous malformations, a congenital vascular anomaly of
CC the central nervous system that can result in hemorrhagic stroke,
CC seizures, recurrent headaches, and focal neurologic deficits. The
CC lesions are characterized by grossly enlarged blood vessels consisting
CC of a single layer of endothelium and without any intervening neural
CC tissue, ranging in diameter from a few millimeters to several
CC centimeters. CCM1 inheritance is autosomal dominant.
CC {ECO:0000269|PubMed:12172908}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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DR EMBL; U90268; AAB58582.1; -; mRNA.
DR EMBL; U90269; AAC01535.1; -; Genomic_DNA.
DR EMBL; AF310133; AAG47774.1; -; mRNA.
DR EMBL; AF296765; AAG10220.2; -; mRNA.
DR EMBL; AF388384; AAM19465.1; -; mRNA.
DR EMBL; AY380057; AAQ94072.1; -; mRNA.
DR EMBL; AK055305; BAG51497.1; -; mRNA.
DR EMBL; AC000120; AAS07420.1; -; Genomic_DNA.
DR EMBL; BC094684; AAH94684.1; -; mRNA.
DR EMBL; BC098442; AAH98442.1; -; mRNA.
DR EMBL; AJ294850; CAC17608.1; -; mRNA.
DR EMBL; AY993945; AAY25568.1; -; Genomic_DNA.
DR CCDS; CCDS34679.1; -. [O00522-3]
DR CCDS; CCDS5624.1; -. [O00522-1]
DR RefSeq; NP_001013424.1; NM_001013406.1. [O00522-3]
DR RefSeq; NP_004903.2; NM_004912.3. [O00522-1]
DR RefSeq; NP_919436.1; NM_194454.1. [O00522-1]
DR RefSeq; NP_919437.1; NM_194455.1. [O00522-1]
DR RefSeq; NP_919438.1; NM_194456.1. [O00522-1]
DR RefSeq; XP_005250717.1; XM_005250660.3.
DR RefSeq; XP_005250719.1; XM_005250662.3.
DR RefSeq; XP_005250722.1; XM_005250665.3.
DR RefSeq; XP_005250723.1; XM_005250666.3.
DR RefSeq; XP_005250724.1; XM_005250667.2.
DR RefSeq; XP_005250725.1; XM_005250668.3.
DR RefSeq; XP_005250726.1; XM_005250669.3.
DR RefSeq; XP_006716224.1; XM_006716161.3.
DR RefSeq; XP_006716225.1; XM_006716162.3.
DR RefSeq; XP_006716226.1; XM_006716163.3.
DR RefSeq; XP_011514953.1; XM_011516651.2.
DR RefSeq; XP_011514955.1; XM_011516653.2.
DR RefSeq; XP_011514956.1; XM_011516654.2.
DR RefSeq; XP_011514957.1; XM_011516655.2.
DR RefSeq; XP_011514958.1; XM_011516656.2.
DR RefSeq; XP_011514959.1; XM_011516657.2.
DR RefSeq; XP_011514960.1; XM_011516658.2.
DR RefSeq; XP_011514961.1; XM_011516659.2.
DR RefSeq; XP_011514962.1; XM_011516660.2.
DR RefSeq; XP_011514963.1; XM_011516661.2.
DR RefSeq; XP_016868244.1; XM_017012755.1.
DR RefSeq; XP_016868245.1; XM_017012756.1.
DR RefSeq; XP_016868246.1; XM_017012757.1.
DR PDB; 3U7D; X-ray; 2.49 A; A/C=417-736.
DR PDB; 4DX8; X-ray; 2.54 A; H/I/J/K=1-198.
DR PDB; 4DXA; X-ray; 1.95 A; B=420-736.
DR PDB; 4HDO; X-ray; 1.67 A; A=417-736.
DR PDB; 4HDQ; X-ray; 1.95 A; A=417-736.
DR PDB; 4JIF; X-ray; 1.70 A; B=170-198.
DR PDB; 4TKN; X-ray; 3.00 A; D/E/F=225-237.
DR PDB; 5D68; X-ray; 2.91 A; A/B/C=259-736.
DR PDB; 6OQ3; X-ray; 1.85 A; A=417-736.
DR PDB; 6OQ4; X-ray; 1.75 A; A=417-736.
DR PDB; 6UZK; X-ray; 1.92 A; A=417-736.
DR PDBsum; 3U7D; -.
DR PDBsum; 4DX8; -.
DR PDBsum; 4DXA; -.
DR PDBsum; 4HDO; -.
DR PDBsum; 4HDQ; -.
DR PDBsum; 4JIF; -.
DR PDBsum; 4TKN; -.
DR PDBsum; 5D68; -.
DR PDBsum; 6OQ3; -.
DR PDBsum; 6OQ4; -.
DR PDBsum; 6UZK; -.
DR AlphaFoldDB; O00522; -.
DR SMR; O00522; -.
DR BioGRID; 107330; 44.
DR ComplexPortal; CPX-983; ICAP1-KRIT1 integrin activation complex.
DR ComplexPortal; CPX-984; CCM endothelial permeability complex.
DR CORUM; O00522; -.
DR DIP; DIP-40610N; -.
DR IntAct; O00522; 10.
DR STRING; 9606.ENSP00000378015; -.
DR iPTMnet; O00522; -.
DR PhosphoSitePlus; O00522; -.
DR BioMuta; KRIT1; -.
DR EPD; O00522; -.
DR jPOST; O00522; -.
DR MassIVE; O00522; -.
DR MaxQB; O00522; -.
DR PaxDb; O00522; -.
DR PeptideAtlas; O00522; -.
DR PRIDE; O00522; -.
DR ProteomicsDB; 47953; -. [O00522-1]
DR ProteomicsDB; 47954; -. [O00522-2]
DR ProteomicsDB; 47955; -. [O00522-3]
DR Antibodypedia; 15587; 206 antibodies from 27 providers.
DR DNASU; 889; -.
DR Ensembl; ENST00000340022.6; ENSP00000344668.2; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000394503.6; ENSP00000378011.2; ENSG00000001631.17. [O00522-3]
DR Ensembl; ENST00000394505.7; ENSP00000378013.2; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000394507.5; ENSP00000378015.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000412043.6; ENSP00000410909.2; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000425073.2; ENSP00000404790.2; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000444960.6; ENSP00000388076.2; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000458177.7; ENSP00000391675.2; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000686094.1; ENSP00000510015.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000686527.1; ENSP00000509139.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000687135.1; ENSP00000509617.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000688404.1; ENSP00000509939.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000688665.1; ENSP00000509209.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000689556.1; ENSP00000508543.1; ENSG00000001631.17. [O00522-3]
DR Ensembl; ENST00000690529.1; ENSP00000510733.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000690720.1; ENSP00000509832.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000690908.1; ENSP00000510110.1; ENSG00000001631.17. [O00522-3]
DR Ensembl; ENST00000692157.1; ENSP00000509514.1; ENSG00000001631.17. [O00522-1]
DR Ensembl; ENST00000692807.1; ENSP00000508564.1; ENSG00000001631.17. [O00522-1]
DR GeneID; 889; -.
DR KEGG; hsa:889; -.
DR MANE-Select; ENST00000394505.7; ENSP00000378013.2; NM_194454.3; NP_919436.1.
DR UCSC; uc003ulr.2; human. [O00522-1]
DR CTD; 889; -.
DR DisGeNET; 889; -.
DR GeneCards; KRIT1; -.
DR GeneReviews; KRIT1; -.
DR HGNC; HGNC:1573; KRIT1.
DR HPA; ENSG00000001631; Low tissue specificity.
DR MalaCards; KRIT1; -.
DR MIM; 116860; phenotype.
DR MIM; 604214; gene.
DR neXtProt; NX_O00522; -.
DR OpenTargets; ENSG00000001631; -.
DR Orphanet; 221061; Familial cerebral cavernous malformation.
DR PharmGKB; PA26144; -.
DR VEuPathDB; HostDB:ENSG00000001631; -.
DR eggNOG; KOG4335; Eukaryota.
DR GeneTree; ENSGT00530000063721; -.
DR HOGENOM; CLU_022188_0_0_1; -.
DR InParanoid; O00522; -.
DR OMA; ICELHIR; -.
DR OrthoDB; 839317at2759; -.
DR PhylomeDB; O00522; -.
DR TreeFam; TF317921; -.
DR BioCyc; MetaCyc:ENSG00000001631-MON; -.
DR PathwayCommons; O00522; -.
DR SignaLink; O00522; -.
DR BioGRID-ORCS; 889; 10 hits in 1084 CRISPR screens.
DR ChiTaRS; KRIT1; human.
DR GeneWiki; KRIT1; -.
DR GenomeRNAi; 889; -.
DR Pharos; O00522; Tbio.
DR PRO; PR:O00522; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; O00522; protein.
DR Bgee; ENSG00000001631; Expressed in calcaneal tendon and 106 other tissues.
DR ExpressionAtlas; O00522; baseline and differential.
DR Genevisible; O00522; HS.
DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0030695; F:GTPase regulator activity; TAS:ProtInc.
DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0045454; P:cell redox homeostasis; IMP:UniProtKB.
DR GO; GO:0003158; P:endothelium development; IC:ComplexPortal.
DR GO; GO:0033622; P:integrin activation; IDA:ComplexPortal.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IMP:UniProtKB.
DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IMP:UniProtKB.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IMP:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; IEA:Ensembl.
DR GO; GO:0045765; P:regulation of angiogenesis; IC:ComplexPortal.
DR GO; GO:2000114; P:regulation of establishment of cell polarity; IMP:UniProtKB.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:ProtInc.
DR CDD; cd14473; FERM_B-lobe; 1.
DR CDD; cd13197; FERM_C_CCM1; 1.
DR DisProt; DP01333; -.
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; -; 2.
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; PF13857; Ank_5; 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 3D-structure; Alternative splicing; Angiogenesis; ANK repeat;
KW Cell junction; Cell membrane; Cytoplasm; Cytoskeleton; Disease variant;
KW Membrane; Reference proteome; Repeat.
FT CHAIN 1..736
FT /note="Krev interaction trapped protein 1"
FT /id="PRO_0000067023"
FT REPEAT 287..316
FT /note="ANK 1"
FT /evidence="ECO:0000255"
FT REPEAT 320..350
FT /note="ANK 2"
FT /evidence="ECO:0000255"
FT REPEAT 354..383
FT /note="ANK 3"
FT /evidence="ECO:0000255"
FT REPEAT 388..419
FT /note="ANK 4"
FT /evidence="ECO:0000255"
FT DOMAIN 420..734
FT /note="FERM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00084"
FT REGION 1..170
FT /note="N-terminal domain similar to Nudix hydrolase domain"
FT REGION 172..195
FT /note="Interaction with ITGB1BP1"
FT REGION 430..452
FT /note="Interaction with RAP1B"
FT /evidence="ECO:0000269|PubMed:22577140"
FT VAR_SEQ 1..207
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9285558"
FT /id="VSP_015800"
FT VAR_SEQ 283..330
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043327"
FT VARIANT 97
FT /note="F -> S (in CCM1)"
FT /evidence="ECO:0000269|PubMed:12172908"
FT /id="VAR_023573"
FT VARIANT 569
FT /note="K -> E (in CCM1)"
FT /evidence="ECO:0000269|PubMed:12172908"
FT /id="VAR_023574"
FT MUTAGEN 47..50
FT /note="KKRK->AAAA: Reduces interaction with microtubules,
FT but not with ITGB1BP1."
FT /evidence="ECO:0000269|PubMed:17916086"
FT MUTAGEN 176
FT /note="A->D: Strongly reduces ITGB1BP1 binding; when
FT associated with D-182."
FT /evidence="ECO:0000269|PubMed:23317506"
FT MUTAGEN 179
FT /note="R->A: Strongly reduces ITGB1BP1 binding; when
FT associated with A-179."
FT /evidence="ECO:0000269|PubMed:23317506"
FT MUTAGEN 182
FT /note="P->D: Strongly reduces ITGB1BP1 binding; when
FT associated with D-176."
FT /evidence="ECO:0000269|PubMed:23317506"
FT MUTAGEN 185
FT /note="R->A: Strongly reduces ITGB1BP1 binding; when
FT associated with A-179."
FT /evidence="ECO:0000269|PubMed:23317506"
FT MUTAGEN 192..195
FT /note="NPAY->APAA: Reduces interaction with ITGB1BP1."
FT /evidence="ECO:0000269|PubMed:17916086"
FT MUTAGEN 192
FT /note="N->A: Reduces ITGB1BP1 binding; when associated with
FT A-195."
FT /evidence="ECO:0000269|PubMed:11741838,
FT ECO:0000269|PubMed:11854171, ECO:0000269|PubMed:23317506"
FT MUTAGEN 195
FT /note="Y->A: Reduces ITGB1BP1 binding; when associated with
FT A-192."
FT /evidence="ECO:0000269|PubMed:11741838,
FT ECO:0000269|PubMed:11854171, ECO:0000269|PubMed:23317506"
FT MUTAGEN 430
FT /note="S->E: Impairs interaction with RAP1B."
FT /evidence="ECO:0000269|PubMed:22577140"
FT MUTAGEN 432
FT /note="R->E: Impairs interaction with RAP1B."
FT /evidence="ECO:0000269|PubMed:22577140"
FT MUTAGEN 452
FT /note="R->E: 40-fold-reduced affinity for Rap1A."
FT /evidence="ECO:0000269|PubMed:21633110,
FT ECO:0000269|PubMed:22577140"
FT MUTAGEN 452
FT /note="R->E: Impairs interaction with RAP1B."
FT /evidence="ECO:0000269|PubMed:21633110,
FT ECO:0000269|PubMed:22577140"
FT MUTAGEN 717
FT /note="L->A: Strongly reduced affinity for HEG1; when
FT associated with A-721."
FT /evidence="ECO:0000269|PubMed:23007647"
FT MUTAGEN 721
FT /note="L->A: Strongly reduced affinity for HEG1; when
FT associated with A-717."
FT /evidence="ECO:0000269|PubMed:23007647"
FT CONFLICT 138
FT /note="I -> T (in Ref. 5; AAQ94072)"
FT /evidence="ECO:0000305"
FT CONFLICT 234
FT /note="F -> G (in Ref. 1; AAB58582)"
FT /evidence="ECO:0000305"
FT CONFLICT 731
FT /note="P -> A (in Ref. 1; AAB58582, 2; AAG47774 and 5;
FT AAQ94072)"
FT /evidence="ECO:0000305"
FT STRAND 9..17
FT /evidence="ECO:0007829|PDB:4DX8"
FT HELIX 30..32
FT /evidence="ECO:0007829|PDB:4DX8"
FT STRAND 33..39
FT /evidence="ECO:0007829|PDB:4DX8"
FT STRAND 54..57
FT /evidence="ECO:0007829|PDB:4DX8"
FT HELIX 64..75
FT /evidence="ECO:0007829|PDB:4DX8"
FT STRAND 92..98
FT /evidence="ECO:0007829|PDB:4DX8"
FT STRAND 107..114
FT /evidence="ECO:0007829|PDB:4DX8"
FT STRAND 131..134
FT /evidence="ECO:0007829|PDB:4DX8"
FT HELIX 135..141
FT /evidence="ECO:0007829|PDB:4DX8"
FT HELIX 151..170
FT /evidence="ECO:0007829|PDB:4DX8"
FT HELIX 173..178
FT /evidence="ECO:0007829|PDB:4DX8"
FT HELIX 182..185
FT /evidence="ECO:0007829|PDB:4JIF"
FT STRAND 186..191
FT /evidence="ECO:0007829|PDB:4JIF"
FT HELIX 193..195
FT /evidence="ECO:0007829|PDB:4JIF"
FT TURN 232..235
FT /evidence="ECO:0007829|PDB:4TKN"
FT HELIX 291..297
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 301..309
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 324..330
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 334..342
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 358..364
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 368..376
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 392..399
FT /evidence="ECO:0007829|PDB:5D68"
FT HELIX 404..412
FT /evidence="ECO:0007829|PDB:5D68"
FT STRAND 415..417
FT /evidence="ECO:0007829|PDB:5D68"
FT STRAND 421..425
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 431..435
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 439..441
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 444..449
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 455..458
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 461..467
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 470..473
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 480..485
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 487..494
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 499..501
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 505..510
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 516..519
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 525..541
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 548..563
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 568..571
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 572..574
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 578..581
FT /evidence="ECO:0007829|PDB:4HDO"
FT TURN 582..584
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 587..589
FT /evidence="ECO:0007829|PDB:4HDO"
FT TURN 590..593
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 594..596
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 598..610
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 612..614
FT /evidence="ECO:0007829|PDB:6UZK"
FT HELIX 618..629
FT /evidence="ECO:0007829|PDB:4HDO"
FT TURN 633..636
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 638..645
FT /evidence="ECO:0007829|PDB:4HDO"
FT TURN 650..652
FT /evidence="ECO:0007829|PDB:4HDQ"
FT STRAND 655..662
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 664..671
FT /evidence="ECO:0007829|PDB:4HDO"
FT TURN 672..674
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 677..682
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 685..690
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 694..701
FT /evidence="ECO:0007829|PDB:4HDO"
FT TURN 702..705
FT /evidence="ECO:0007829|PDB:4HDO"
FT STRAND 706..711
FT /evidence="ECO:0007829|PDB:4HDO"
FT HELIX 715..728
FT /evidence="ECO:0007829|PDB:4HDO"
SQ SEQUENCE 736 AA; 84348 MW; D11F75ED629E85AC CRC64;
MGNPENIEDA YVAVIRPKNT ASLNSREYRA KSYEILLHEV PIEGQKKKRK KVLLETKLQG
NSEITQGILD YVVETTKPIS PANQGIRGKR VVLMKKFPLD GEKMGREASL FIVPSVVKDN
TKYTYTPGCP IFYCLQDIMR VCSESSTHFA TLTARMLIAL DKWLDERHAQ SHFIPALFRP
SPLERIKTNV INPAYATESG QTENSLHMGY SALEIKSKML ALEKADTCIY NPLFGSDLQY
TNRVDKVVIN PYFGLGAPDY SKIQIPKQEK WQRSMSSVTE DKERQWVDDF PLHRSACEGD
SELLSRLLSE RFSVNQLDSD HWAPIHYACW YGKVEATRIL LEKGKCNPNL LNGQLSSPLH
FAAGGGHAEI VQILLNHPET DRHITDQQGR SPLNICEENK QNNWEEAAKL LKEAINKPYE
KVRIYRMDGS YRSVELKHGN NTTVQQIMEG MRLSQETQQY FTIWICSENL SLQLKPYHKP
LQHVRDWPEI LAELTNLDPQ RETPQLFLRR DVRLPLEVEK QIEDPLAILI LFDEARYNLL
KGFYTAPDAK LITLASLLLQ IVYGNYESKK HKQGFLNEEN LKSIVPVTKL KSKAPHWTNR
ILHEYKNLST SEGVSKEMHH LQRMFLQNCW EIPTYGAAFF TGQIFTKASP SNHKVIPVYV
GVNIKGLHLL NMETKALLIS LKYGCFMWQL GDTDTCFQIH SMENKMSFIV HTKQAGLVVK
LLMKLNGQLM PTERNS
