O00522 (KRIT1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	736 AA.
Sequence status	Complete.
Protein existence	Evidence 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.

Ontologies

Keywords
Biological process	Angiogenesis
Cellular component	Cell junction Membrane
Coding sequence diversity	Alternative splicing
Disease	Disease mutation
Domain	ANK repeat Repeat
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW cell redox homeostasis Inferred from mutant phenotype Ref.11. Source: UniProtKB negative regulation of angiogenesis Inferred from mutant phenotype Ref.12. Source: UniProtKB negative regulation of endothelial cell apoptosis Inferred from mutant phenotype Ref.12. Source: UniProtKB negative regulation of endothelial cell migration Inferred from mutant phenotype Ref.12. Source: UniProtKB negative regulation of endothelial cell proliferation Inferred from mutant phenotype Ref.12. Source: UniProtKB regulation of establishment of cell polarity Inferred from mutant phenotype Ref.10. Source: UniProtKB small GTPase mediated signal transduction Traceable author statement. Source: ProtInc
Cellular component	cell-cell junction Inferred from direct assay Ref.10. Source: UniProtKB cytoskeleton Inferred from electronic annotation. Source: InterPro membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	protein binding Inferred from physical interaction Ref.10. Source: UniProtKB small GTPase regulator activity Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CCM2	Q9BSQ5	3	EBI-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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 736	736	Krev interaction trapped protein 1		PRO_0000067023
Regions
	Repeat	287 – 316	30	ANK 1
	Repeat	320 – 350	31	ANK 2
	Repeat	354 – 383	30	ANK 3
	Repeat	388 – 419	32	ANK 4
	Domain	420 – 734	315	FERM
	Region	487 – 736	250	Required for RAP1A-binding
Natural variations
	Alternative sequence	1 – 207	207	Missing in isoform 2.		VSP_015800
	Natural variant	97	1	F → S in CCM1. Ref.4		VAR_023573
	Natural variant	569	1	K → E in CCM1. Ref.4		VAR_023574
Experimental info
	Sequence conflict	138	1	I → T in AAQ94072. Ref.5
	Sequence conflict	234	1	F → G in AAB58582. Ref.1
	Sequence conflict	731	1	P → A in AAB58582. Ref.1
	Sequence conflict	731	1	P → A in AAG47774. Ref.2
	Sequence conflict	731	1	P → A in AAQ94072. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 11, 2005. Version 2. Checksum: D11F75ED629E85AC	FASTA	736	84,348
	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
	Isoform 2 [UniParc]. Checksum: D56082828EEB7094	FASTA	529	60,945
	10 20 30 40 50 60 MGYSALEIKS KMLALEKADT CIYNPLFGSD LQYTNRVDKV VINPYFGLGA PDYSKIQIPK 70 80 90 100 110 120 QEKWQRSMSS VTEDKERQWV DDFPLHRSAC EGDSELLSRL LSERFSVNQL DSDHWAPIHY 130 140 150 160 170 180 ACWYGKVEAT RILLEKGKCN PNLLNGQLSS PLHFAAGGGH AEIVQILLNH PETDRHITDQ 190 200 210 220 230 240 QGRSPLNICE ENKQNNWEEA AKLLKEAINK PYEKVRIYRM DGSYRSVELK HGNNTTVQQI 250 260 270 280 290 300 MEGMRLSQET QQYFTIWICS ENLSLQLKPY HKPLQHVRDW PEILAELTNL DPQRETPQLF 310 320 330 340 350 360 LRRDVRLPLE VEKQIEDPLA ILILFDEARY NLLKGFYTAP DAKLITLASL LLQIVYGNYE 370 380 390 400 410 420 SKKHKQGFLN EENLKSIVPV TKLKSKAPHW TNRILHEYKN LSTSEGVSKE MHHLQRMFLQ 430 440 450 460 470 480 NCWEIPTYGA AFFTGQIFTK ASPSNHKVIP VYVGVNIKGL HLLNMETKAL LISLKYGCFM 490 500 510 520 WQLGDTDTCF QIHSMENKMS FIVHTKQAGL VVKLLMKLNG QLMPTERNS

References

	« Hide 'large scale' referencesShow '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. , 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

GeneReviews

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.
IPI	IPI00418142. IPI00651671.
RefSeq	NP_004903.2. NM_004912.3. NP_919436.1. NM_194454.1. NP_919437.1. NM_194455.1. NP_919438.1. NM_194456.1.
UniGene	Hs.531987.
3D structure databases
ProteinModelPortal	O00522.
SMR	O00522. Positions 208-446.
ModBase	Search...
Protein-protein interaction databases
IntAct	O00522. 4 interactions.
STRING	O00522.
PTM databases
PhosphoSite	O00522.
Proteomic databases
PRIDE	O00522.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000340022; ENSP00000344668; ENSG00000001631. ENST00000394505; ENSP00000378013; ENSG00000001631. ENST00000394507; ENSP00000378015; ENSG00000001631. ENST00000412043; ENSP00000410909; ENSG00000001631.
GeneID	889.
KEGG	hsa:889.
UCSC	uc003ulq.1. human. uc010lev.1. human.
Organism-specific databases
CTD	889.
GeneCards	GC07M091828.
H-InvDB	HIX0006839.
HGNC	HGNC:1573. KRIT1.
HPA	HPA022155.
MIM	116860. phenotype. 604214. gene.
neXtProt	NX_O00522.
Orphanet	221061. Hereditary cerebral cavernous malformation.
GenAtlas	Search...
Phylogenomic databases
GeneTree	ENSGT00530000063721.
HOVERGEN	HBG052292.
InParanoid	O00522.
OMA	SKAPHWT.
OrthoDB	EOG4V1706.
PhylomeDB	O00522.
Gene expression databases
ArrayExpress	O00522.
Bgee	O00522.
CleanEx	HS_KRIT1.
Genevestigator	O00522.
GermOnline	ENSG00000001631. Homo sapiens.
Family and domain databases
InterPro	IPR002110. 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]
Gene3D	G3DSA:1.20.80.10. ACBP. 1 hit. G3DSA:1.25.40.20. ANK. 1 hit.
Pfam	PF12796. Ank_2. 1 hit. PF00373. FERM_M. 1 hit. [Graphical view]
SMART	SM00248. ANK. 3 hits. SM00295. B41. 1 hit. [Graphical view]
SUPFAM	SSF48403. ANK. 1 hit. SSF47031. FERM_3-hlx. 1 hit.
PROSITE	PS50297. 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]
ProtoNet	Search...
Other
NextBio	3670.
SOURCE	Search...

Entry information

Entry name

KRIT1_HUMAN

Accession

Primary (citable) accession number: O00522
Secondary accession number(s): O43894 , 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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.