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O00522 (KRIT1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 112. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Krev interaction trapped protein 1

Short name=Krev interaction trapped 1
Alternative name(s):
Cerebral cavernous malformations 1 protein
Gene names
Name:KRIT1
Synonyms:CCM1
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length736 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity By similarity. Negative regulator of angiogenesis. Inhibits endothelial proliferation, apoptosis, migration, lumen formation and sprouting angiogenesis in primary endothelial cells. Promotes AKT phosphorylation in a NOTCH-dependent and independent manner, and inhibits EKR1/2 phosphorylation indirectly through activation of the DELTA-NOTCH cascade. Acts in concert with CDH5 to establish and maintain correct endothelial cell polarity and vascular lumen and these effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction. Plays an important role in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage. Regulates the homeostasis of intracellular ROS through an antioxidant pathway involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1 (CCND1) levels required for cell transition from proliferative growth to quiescence by preventing the accumulation of intracellular ROS through the modulation of FOXO1 and SOD2 levels.

Subunit structure

Interacts with RAP1A. Interacts with CDH5. Interacts with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1 By similarity. Ref.1 Ref.10

Subcellular location

Membrane; Peripheral membrane protein Probable. Cell junction. Note: KRIT1 and CDH5 reciprocally regulate their localization to endothelial cell-cell junctions. Ref.10

Tissue specificity

Low levels in brain. Very weak expression found in heart and muscle. Ref.1

Involvement in disease

Defects in KRIT1 are the cause of cerebral cavernous malformations type 1 (CCM1) [MIM:116860]. Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. CCMs have an incidence of 0.1%-0.5% in the general population and usually present clinically during the 3rd to 5th decade of life. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. Ref.4

Sequence similarities

Contains 4 ANK repeats.

Contains 1 FERM domain.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

CCM2Q9BSQ53EBI-1573121,EBI-1573056

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O00522-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O00522-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-207: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 736736Krev interaction trapped protein 1
PRO_0000067023

Regions

Repeat287 – 31630ANK 1
Repeat320 – 35031ANK 2
Repeat354 – 38330ANK 3
Repeat388 – 41932ANK 4
Domain420 – 734315FERM
Region487 – 736250Required for RAP1A-binding

Natural variations

Alternative sequence1 – 207207Missing in isoform 2.
VSP_015800
Natural variant971F → S in CCM1. Ref.4
VAR_023573
Natural variant5691K → E in CCM1. Ref.4
VAR_023574

Experimental info

Sequence conflict1381I → T in AAQ94072. Ref.5
Sequence conflict2341F → G in AAB58582. Ref.1
Sequence conflict7311P → A in AAB58582. Ref.1
Sequence conflict7311P → A in AAG47774. Ref.2
Sequence conflict7311P → A in AAQ94072. Ref.5

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 11, 2005. Version 2.
Checksum: D11F75ED629E85AC

FASTA73684,348
        10         20         30         40         50         60 
MGNPENIEDA YVAVIRPKNT ASLNSREYRA KSYEILLHEV PIEGQKKKRK KVLLETKLQG 

        70         80         90        100        110        120 
NSEITQGILD YVVETTKPIS PANQGIRGKR VVLMKKFPLD GEKMGREASL FIVPSVVKDN 

       130        140        150        160        170        180 
TKYTYTPGCP IFYCLQDIMR VCSESSTHFA TLTARMLIAL DKWLDERHAQ SHFIPALFRP 

       190        200        210        220        230        240 
SPLERIKTNV INPAYATESG QTENSLHMGY SALEIKSKML ALEKADTCIY NPLFGSDLQY 

       250        260        270        280        290        300 
TNRVDKVVIN PYFGLGAPDY SKIQIPKQEK WQRSMSSVTE DKERQWVDDF PLHRSACEGD 

       310        320        330        340        350        360 
SELLSRLLSE RFSVNQLDSD HWAPIHYACW YGKVEATRIL LEKGKCNPNL LNGQLSSPLH 

       370        380        390        400        410        420 
FAAGGGHAEI VQILLNHPET DRHITDQQGR SPLNICEENK QNNWEEAAKL LKEAINKPYE 

       430        440        450        460        470        480 
KVRIYRMDGS YRSVELKHGN NTTVQQIMEG MRLSQETQQY FTIWICSENL SLQLKPYHKP 

       490        500        510        520        530        540 
LQHVRDWPEI LAELTNLDPQ RETPQLFLRR DVRLPLEVEK QIEDPLAILI LFDEARYNLL 

       550        560        570        580        590        600 
KGFYTAPDAK LITLASLLLQ IVYGNYESKK HKQGFLNEEN LKSIVPVTKL KSKAPHWTNR 

       610        620        630        640        650        660 
ILHEYKNLST SEGVSKEMHH LQRMFLQNCW EIPTYGAAFF TGQIFTKASP SNHKVIPVYV 

       670        680        690        700        710        720 
GVNIKGLHLL NMETKALLIS LKYGCFMWQL GDTDTCFQIH SMENKMSFIV HTKQAGLVVK 

       730 
LLMKLNGQLM PTERNS 

« Hide

Isoform 2 [UniParc].

Checksum: D56082828EEB7094
Show »

FASTA52960,945

References

« Hide 'large scale' references
[1]"Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22."
Serebriiskii I., Estojak J., Sonoda G., Testa J.R., Golemis E.A.
Oncogene 15:1043-1049(1997) [PubMed: 9285558] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), TISSUE SPECIFICITY, INTERACTION WITH RAP1A.
Tissue: Kidney and Mammary cancer.
[2]"Cloning of the murine Krit1 cDNA reveals novel mammalian 5' coding exons."
Zhang J., Clatterbuck R.E., Rigamonti D., Dietz H.C.
Genomics 70:392-395(2000) [PubMed: 11161791] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]"Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene."
Sahoo T., Goenaga-Diaz E., Serebriiskii I.G., Thomas J.W., Kotova E., Cuellar J.G., Peloquin J.M., Golemis E., Beitinjaneh F., Green E.D., Johnson E.W., Marchuk D.A.
Genomics 71:123-126(2001) [PubMed: 11161805] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ALTERNATIVE SPLICING.
[4]"Mutation and expression analysis of the KRIT1 gene associated with cerebral cavernous malformations (CCM1)."
Kehrer-Sawatzki H., Wilda M., Braun V.M., Richter H.-P., Hameister H.
Acta Neuropathol. 104:231-240(2002) [PubMed: 12172908] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ALTERNATIVE SPLICING, VARIANTS CCM1 SER-97 AND GLU-569.
[5]"Four novel and three known KRIT1 mutations in CCM Italian patients: Characterization at mRNA and protein level."
Ferrera L., Marini V., Dorcaratto A., Pigatto F., Alberti F., Forni M., Cama A., Viale G., Origone P., Mareni C., Garre' C.
Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]"The DNA sequence of human chromosome 7."
Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. expand/collapse author list , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K.
Nature 424:157-164(2003) [PubMed: 12853948] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain and Uterus.
[8]"Identification of eight novel 5`-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1."
Eerola I., McIntyre B., Vikkula M.
Biochim. Biophys. Acta 1517:464-467(2001) [PubMed: 11342228] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-243, ALTERNATIVE SPLICING.
[9]"Six novel and three known KRIT1 mutations in CCM patients: characterization at mRNA level."
Marini V., Ferrera L., Dorcaratto A., Forni M., Capra V., Origone P., Mareni C., Garre' C.
Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 244-281.
[10]"CCM1 regulates vascular-lumen organization by inducing endothelial polarity."
Lampugnani M.G., Orsenigo F., Rudini N., Maddaluno L., Boulday G., Chapon F., Dejana E.
J. Cell Sci. 123:1073-1080(2010) [PubMed: 20332120] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH CDH5.
[11]"KRIT1 regulates the homeostasis of intracellular reactive oxygen species."
Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P., Retta S.F.
PLoS ONE 5:E11786-E11786(2010) [PubMed: 20668652] [Abstract]
Cited for: FUNCTION.
[12]"Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling."
Wuestehube J., Bartol A., Liebler S.S., Bruetsch R., Zhu Y., Felbor U., Sure U., Augustin H.G., Fischer A.
Proc. Natl. Acad. Sci. U.S.A. 107:12640-12645(2010) [PubMed: 20616044] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U90268 mRNA. Translation: AAB58582.1.
U90269 Genomic DNA. Translation: AAC01535.1.
AF310133 mRNA. Translation: AAG47774.1.
AF296765 mRNA. Translation: AAG10220.2.
AF388384 mRNA. Translation: AAM19465.1.
AY380057 mRNA. Translation: AAQ94072.1.
AC000120 Genomic DNA. Translation: AAS07420.1.
BC094684 mRNA. Translation: AAH94684.1.
BC098442 mRNA. Translation: AAH98442.1.
AJ294850 mRNA. Translation: CAC17608.1.
AY993945 Genomic DNA. Translation: AAY25568.1.
IPIIPI00418142.
IPI00651671.
RefSeqNP_004903.2. NM_004912.3.
NP_919436.1. NM_194454.1.
NP_919437.1. NM_194455.1.
NP_919438.1. NM_194456.1.
UniGeneHs.531987.

3D structure databases

ProteinModelPortalO00522.
SMRO00522. Positions 208-446.
ModBaseSearch...

Protein-protein interaction databases

IntActO00522. 4 interactions.
STRINGO00522.

PTM databases

PhosphoSiteO00522.

Proteomic databases

PRIDEO00522.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000340022; ENSP00000344668; ENSG00000001631.
ENST00000394505; ENSP00000378013; ENSG00000001631.
ENST00000394507; ENSP00000378015; ENSG00000001631.
ENST00000412043; ENSP00000410909; ENSG00000001631.
GeneID889.
KEGGhsa:889.
UCSCuc003ulq.1. human.
uc010lev.1. human.

Organism-specific databases

CTD889.
GeneCardsGC07M091828.
H-InvDBHIX0006839.
HGNCHGNC:1573. KRIT1.
HPAHPA022155.
MIM116860. phenotype.
604214. gene.
neXtProtNX_O00522.
Orphanet221061. Hereditary cerebral cavernous malformation.
GenAtlasSearch...

Phylogenomic databases

GeneTreeENSGT00530000063721.
HOVERGENHBG052292.
InParanoidO00522.
OMASKAPHWT.
OrthoDBEOG4V1706.
PhylomeDBO00522.

Gene expression databases

ArrayExpressO00522.
BgeeO00522.
CleanExHS_KRIT1.
GenevestigatorO00522.
GermOnlineENSG00000001631. Homo sapiens.

Family and domain databases

InterProIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
IPR019749. Band_41_domain.
IPR014352. FERM/acyl-CoA-bd_prot_3-hlx.
IPR019748. FERM_central.
IPR000299. FERM_domain.
[Graphical view]
Gene3DG3DSA:1.20.80.10. ACBP. 1 hit.
G3DSA:1.25.40.20. ANK. 1 hit.
PfamPF12796. Ank_2. 1 hit.
PF00373. FERM_M. 1 hit.
[Graphical view]
SMARTSM00248. ANK. 3 hits.
SM00295. B41. 1 hit.
[Graphical view]
SUPFAMSSF48403. ANK. 1 hit.
SSF47031. FERM_3-hlx. 1 hit.
PROSITEPS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. 1 hit.
PS00660. FERM_1. False negative.
PS00661. FERM_2. False negative.
PS50057. FERM_3. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio3670.
SOURCESearch...

Entry information

Entry nameKRIT1_HUMAN
AccessionPrimary (citable) accession number: O00522
Secondary accession number(s): O43894 expand/collapse secondary AC list , Q506L6, Q6U276, Q75N19, Q9H180, Q9H264, Q9HAX5
Entry history
Integrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: October 11, 2005
Last modified: January 25, 2012
This is version 112 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

Human chromosome 7

Human chromosome 7: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families