KRIT1_BOVIN
ID KRIT1_BOVIN Reviewed; 736 AA.
AC Q6TNJ1;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 25-MAY-2022, entry version 105.
DE RecName: Full=Krev interaction trapped protein 1;
DE Short=Krev interaction trapped 1;
DE AltName: Full=Cerebral cavernous malformations 1 protein homolog;
GN Name=KRIT1; Synonyms=CCM1;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Zhang J., Basu S., Rigamonti D., Clatterbuck R.E., Dietz H.C.;
RT "Molecular and cellular biology of CCM.";
RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
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. 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. Plays an important
CC role in the maintenance of the intracellular reactive oxygen species
CC (ROS) homeostasis to prevent oxidative cellular damage. Regulates the
CC homeostasis of intracellular ROS through an antioxidant pathway
CC involving FOXO1 and SOD2. Facilitates the down-regulation of cyclin-D1
CC (CCND1) levels required for cell transition from proliferative growth
CC to quiescence by preventing the accumulation of intracellular ROS
CC through the modulation of FOXO1 and SOD2 levels. Microtubule-associated
CC protein that binds to phosphatidylinositol 4,5-bisphosphate (PIP2)-
CC containing membranes in a GTP-bound RAP1-dependent manner (By
CC similarity). May play a role in the regulation of macroautophagy
CC through the down-regulation of the mTOR pathway (By similarity).
CC {ECO:0000250|UniProtKB:O00522, ECO:0000250|UniProtKB:Q6S5J6}.
CC -!- SUBUNIT: Found in a complex, at least composed of ITGB1BP1, KRIT1 and
CC RAP1A. Interacts (via C-terminus FERM domain) with RAP1A (active GTP-
CC bound form preferentially); the interaction does not induce the opening
CC conformation of KRIT1. Interacts (via N-terminus NPXY motif) with
CC ITGB1BP1; the interaction induces the opening conformation of KRIT1 and
CC competes with ITGB1 for ITGB1BP1 interaction. Associates (via N-
CC terminus and C-terminus regions) with microtubules; the interaction is
CC inhibited in presence of ITGB1BP1 and active GTP-bound RAP1A. Interacts
CC (via FERM domain) with RAP1B. Interacts with CDH5 (By similarity).
CC Interacts with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1
CC (By similarity). Interacts with RAP1A. {ECO:0000250|UniProtKB:O00522,
CC ECO:0000250|UniProtKB:Q6S5J6}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton {ECO:0000250}. Cell
CC membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. Cell
CC junction {ECO:0000250}. Note=KRIT1 and CDH5 reciprocally regulate their
CC localization to endothelial cell-cell junctions. Association with RAP1
CC relocalizes KRIT1 from microtubules to cell junction membranes.
CC Translocates from the cytoplasm along microtubules to the cell membrane
CC in an ITGB1BP1-dependent manner (By similarity). {ECO:0000250}.
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:0000250|UniProtKB:O00522}.
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:0000250|UniProtKB:O00522}.
CC -!- DOMAIN: Contains 4 ANK repeats that precede the FERM domain.
CC {ECO:0000250|UniProtKB:O00522}.
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DR EMBL; AY391713; AAR27294.1; -; mRNA.
DR RefSeq; NP_001001166.1; NM_001001166.1.
DR AlphaFoldDB; Q6TNJ1; -.
DR SMR; Q6TNJ1; -.
DR STRING; 9913.ENSBTAP00000003566; -.
DR PaxDb; Q6TNJ1; -.
DR PRIDE; Q6TNJ1; -.
DR GeneID; 407996; -.
DR KEGG; bta:407996; -.
DR CTD; 889; -.
DR eggNOG; KOG4335; Eukaryota.
DR InParanoid; Q6TNJ1; -.
DR OrthoDB; 839317at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB.
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:0008017; F:microtubule binding; ISS:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0016525; P:negative regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0010596; P:negative regulation of endothelial cell migration; ISS:UniProtKB.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; ISS:UniProtKB.
DR GO; GO:2000114; P:regulation of establishment of cell polarity; ISS:UniProtKB.
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; -; 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 2: Evidence at transcript level;
KW Angiogenesis; ANK repeat; Cell junction; Cell membrane; Cytoplasm;
KW Cytoskeleton; Membrane; Reference proteome; Repeat.
FT CHAIN 1..736
FT /note="Krev interaction trapped protein 1"
FT /id="PRO_0000067022"
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..384
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 /evidence="ECO:0000250"
FT REGION 172..195
FT /note="Interaction with ITGB1BP1"
FT /evidence="ECO:0000250"
FT REGION 430..452
FT /note="Interaction with RAP1B"
FT /evidence="ECO:0000250"
SQ SEQUENCE 736 AA; 84291 MW; ABDF4F1EC7B36F0C CRC64;
MGNPENIEDA YVAVIRPKNA ASLNSREYRA KSYEILLHEV PIEGQKKKRK KVLLETKLQG
NSEITQGISD YVVETTEPIS PANQGIRGKR VVLMKTFPLE GEKVGREAAL FIVPSVVKDN
TKYTYTPGCP IFYCLQDIMR VCSESSTHFA TLTARMLIAL DKWLDERHTQ SHFIPALFRP
SPLERIKTNV INPAYATESG QAENSLHMGY SALEIKSKML ALEKADTCIY NPLFGSDLQY
TNRVDKVVIN PYFGLGAPDY SKIQIPKQEQ WQRSRSSVTE DKERQWVDDF PLHRSACEGD
SELLNRLLNE RFSVNQLDSD HWAPIHYACW YGKVEATRIL LEKGKCNPNL LNGQLSSPLH
FAAGGGHAEI VQILLNHPEI DRHITDQQGR SPLNICEENK QNNWEEAAKL LKEAINKPYE
KVRIYRMDGS YRSVELKHGN NTTVQQIMEG MRLSQETQQY FTIWICSENL SLQLKPYHKP
LQHVRDWPEI LAELTNLDPQ RETPQLFLRR DVRLPLEVEK KIEDPLAILI LFDEARYNLL
KGFYTAPDAK LITLASLLLQ IVYGNYESKK HKQGFLNEEN LKSIVPITKL KSKAPHWTNR
ILHEYKNLST SEGVSKEMHH LQRMFLQNCW EIPTYGAAFF TGQIFTKASP SNHKVIPVYV
GVNIKGLHLL NMETKALLIS LKYGCFMWQL GDADSCFQIH SMENKMSFIV HTKQAGLVVK
LLVKLNGQLM PMERNS
