Gene: [20p112/THBD] thrombomodulin (endothelial cell trombin receptor); [THRM TM ]
GEN | [1] The
nucleotide sequence of THBD is approximately 3.7 kb, containing 1.7 kb
coding sequence, 0.7 kb 5'- and 2.2 kb 3'-noncoding and/or flanking
sequences. Gene is free of introns in both the coding and the noncoding
regions. [2] In the 5'-flanking region, a tentative TATA box sequence was identified at the nucleotide-196, and a potential CAAT box sequence was found at 83 nucleotides upstream from the TATA box. Four potential binding site sequences (GGGCGG or CCGCCCC) of Sp1, which may play a role in directing late viral transcription from the opposite strand of the DNA (Dynan-1985), were found upstream of the CAAT box. Five sequences of AATAAA were identified in the 3' noncoding and/or flanking region of the gene. There were also identified six other potential consensus sequences of CACTG, which may also be involved in polyadenylation or cleavage of the mRNA at the 3' end (Berget-1984). The poly(A) sequence started at the nucleotide 3509 downstream from the fourth AATAAA sequence, indicating that the fourth AATAAA sequence could be the polyadenylation site that is actually used. [3] The overall organization of the TM gene represents a unique example of a gene that contains epidermal growth factor (GEM:04q25/EGF) type B repeats and a membrane spanning region, which are not isolated within discrete exons." |
FUN | Thrombomodulin is a cell surface cofactor protein on the vascular endothelium that increases the rate of thrombin-catalyzed activation of protein C (02q13/PROC). This specific endothelial cell receptor forms a 1:1 molecular complex with thrombin (Esmon-1981). This interaction product is capable of rapidly converting protein C to activated protein C, which proteolytically destroys the activated cofactors of the coagulation mechanism and thereby dramatically suppresses the amount of thrombin generated. In this complex, thrombin (GEM:11^/F2), in addition to activating protein C, loses its procoagulant activities such as fibrinogen cloting and activation of factor V and platelets (Esmon-1982b, Esmon-1983). Thus, thrombomodulin plays an important role on the luminal surface of the vascule in converting thrombin from a procoagulant to an anticoagulant." |
MOP | [1]
Thrombomodulin is a single chain glycoprotein of MM 78,000 and forms a
noncovalent 1:1 complex with thrombin with a Kd value of 0.00000000048 M
(Esmon-1982a). [2] The amino acid sequence, as deduced from the nucleotide sequence, indicates that thrombomodulin is synthesized as a precursor consisting of 575 amino acids involving an 18-residue (Suzuki-1987) or 16-residue (Jackman-1987) signal peptide. [3] The mature protein is composed of five tentative domains: an amino-terminal domain, a domain with six EGF-like structures, an 0-glycosylation-rich domain, a transmembrane domain, and a cytoplasmic carboxyl terminal domain. This feature of thrombomodulin resembles that of LDL receptor (GEM:19p132/LDLR; Russell-1984) and EGF precursor (Bell-1986)." |
EVO | [1] Thrombomodulin (TM) is structurally similar to
coated pit receptors and is organized into domains that resemble those of
the low density lipoprotein receptor (GEM:19p132/LDLR). The overall features of the amino
acid sequence of human TM are very similar to those of the LDLR
(Suzuki-1987). However, the nucleotide sequence of the two proteins are not
homologous, except for the sequence corresponding to the EGF-like
structures. In the 5'-flanking region of the THBD, a typical TATA box and a
CAAT box are present, while in the LDLR gene (Sudhof-1985) two AT-rich
sequences (TTGAAAT and TGTAAAT) presumably serving as the TATA box sequence
are present, but the typical CAAT box sequence is absent. The THBD gene has
four presumed Sp1 binding site sequences (GGGCGG or CCGCCC) in the
5'-flanking region, but the LDLR gene has not. The most important
difference between the THBD and LDLR genes is that the latter is more than
45 kb in length and contains 17 introns dividing the gene into 18 exons,
while the former appears to be devoid of intron(s). This is not unique
among eukaryotic genes, since several other genes such as those encoding
proteins in mitochondria (Anderson-1981), alpha- and beta-interferon
(Nagata-1980; Tavernier-1981), and angiogenin (GEM:14q11/ANG) are also free of introns. [2] The C-terminal two-thirds of human TM is quite homologous to the similarly designated segment of bovine TM (Jackman-1986). The alignment of the two endothelial cell receptor species within this region reveals a 65% identity of amino acid residues, which increases to 75% when conservative changes are accepted. Detailed examination of the human and bovine TMs shows that the two cytoplasmic tails have only charge-conservative changes from the invariant single cysteine residue at the cytoplasmic boundary to the carboxyl terminus and that the transmembrane regions are more than 90% conserved. This may indicate an important biologic function for this region in endocytosis (Maruyama-1985). The greatest difference between the two TM species is observed to occur in the Ser + Thr-rich region where the human endothelial cell receptor is 20% shorter than the bovine membrane component. However, a central core of 14 amino acid residues is highly conserved between the two TM species, which may be of functional significance, especially if this region is a site of O-linked glycosylation as is the case for the LDL receptor (Sudhof-1985). The six EGF type B repeat domains present in bovine TM are also found within the human TM, with the same average number of amino acid residues between the 6 cysteine residues within a given repeat. Detailed comparisons of these repeat domains revealed that the spacings between only 2 of the 36 cysteine residues of the human endothelial cell receptor are larger by one or two amino acid residues than the similarly designated region on the bovine membrane component. Each TM species also possesses 2 potential sites for N-linked glycosylation within the EGF type B repeat domains. In the human TM, these sites are placed at residues 382 and 409. The more proximal site is identically located on both endothelial cell receptor species, whereas the more distal site is found within the second EGF repeat for the human membrane component, and the fourth EGF repeat for the bovine membrane component." |
MAP | See GEM:20p112/SNAP. |
REF | GEN,EVO "Anderson &: Nature, 290, 451-465, 1981 SEQ "Bell GI &: NAR, 14, 8427-8446, 1986 GEN "Berget SM: Nature, 309, 179-182, 1984 IDN,FUN,EVO "Bourin &: PNAS, 83, N16, 5924-5928, 1986 FUN "Comp, Esmon: J Clin Invest, 68, 1221-1228, 1981 EVO "Cowan &: PNAS, 77,6511-6515, 1981 GEN "Dynan, Tjian: Nature, 316, 774-778, 1985 REV,FUN,STR "Esmon CT: Science, 235, 1348-1352, 1987 IDN,FUN,EVO "Esmon CT &: JBC, 258, 12238-12242, 1983 IDN,FUN,EVO,MOP "Esmon CT &: JBC, 257, 859-864, 1982a IDN,FUN,EVO "Esmon CT &: JBC, 257, 7944-7947, 1982b FUN "Esmon CT, Owen: PNAS, 78, 2249-2252, 1981 REV,FUN,STR "Esmon NL: Semin Thromb Hemost, 13, 454-463, 1987 LOC,MOL "Espinosa &: CCG, 51, (HGM10), 995, 1989 EVO "Firtel RA: Cell, 24, 6-7, 1981 EVO "Gilbert W: Nature, 271, 501, 1978 IDN,FUN,EVO "Ishii, Majerus: J Clin Invest, 76, 2178-2181, 1985 CLO,GEN,SEQ,MOP "Jackman RW &: PNAS, 84, N18, 6425-6429, 1987 EVO "Jackman RW &: PNAS, 83, 8834-8838, 1986 FUN "Kisiel W: J Clin Invest, 64, 761-769, 1979 LOC,MAP "Maglott DR &: Mammal Genome, 7, 400-401, 1996 FUN "Marler &: Blood, 59, 1067-1072, 1982 EVO "Maruyama, Majerus: JBC, 260, 15432-15438, 1985 GEN,EVO "Nagata S &: Nature, 287, 401-408, 1980 EVO "Naora, Deacon: PNAS, 79, 6196-6200, 1982 FUN "Owen, Esmon: JBC, 256, 5532-5535, 1981 SEQ "Russell &: Cell, 37, 577-585, 1984 FUN "Sakata &: J Clin Invest, 82, 1121-1126, 1985 FUN "Stenflo J: JBC, 251, 355-363, 1976 GEN,EVO "Sudhof TC &: Science, 228, 815-822, 1985 CLO,GEN,SEQ,MOP,EVO "Suzuki K &: EMBO J, 6, N7, 1891-1897, 1987 FUN "Suzuki K &: JBC, 258, 1914-1920, 1983 GEN,EVO "Tavernier &: NAR, 9, 461-471, 1981 IDN,FUN,EVO "Thompson, Salem: J Clin Invest, 78, 13-17, 1986 FUN "Vehar, Davie: Biochemistry, 19, 401-410, 1980 CLO,SEQ,EXP,LOC "Wen OZ &: Biochemistry, 26, 4350-4357, 1987 |
SWI | SWISSPROT: P07204 |
KEY | hem, clot, card, recp |
CLA | coding, basic |
LOC | 20 p11.2 |
MIM | MIM: 188040 |
SYN | THRM TM |
