TGFR1_HUMAN » TGF-beta receptor type-1

TGFR1_HUMAN » TGF-beta receptor type-1
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Topology in Plasma membrane
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cytoplasmic side
TGFR1_HUMAN » TGF-beta receptor type-1 » TGFR-1; Activin A receptor type II-like protein kinase of 53kD;Activin receptor-like kinase 5;ALK-5; ALK5; Serine/threonine-protein kinase receptor R4;SKR4; TGF-beta type I receptor;Transforming growth factor-beta receptor type I;TGF-beta receptor type I;
Hydrophobic Thickness 29.6 ± 2.8 Å
Tilt Angle 0 ± 1°
ΔGtransfer -34.9 kcal/mol
ΔGfold -13.9 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 123-148 (123-151)
Pathways

Adherens junction (KEGG)

Chagas disease (KEGG)

Chronic myeloid leukemia (KEGG)

Colorectal cancer (KEGG)

Cytokine-cytokine receptor interaction (KEGG)

Endocytosis (KEGG)

Hepatitis B (KEGG)

Hippo signaling pathway (KEGG)

HTLV-I infection (KEGG)

MAPK signaling pathway (KEGG)

Osteoclast differentiation (KEGG)

Pancreatic cancer (KEGG)

Pathways in cancer (KEGG)

Signal Transduction (Reactome)

TGF-beta signaling pathway (KEGG)

PDB 3faa (162-503), 3kcf (162-503), 2x7o (162-503), 1py5 (175-500), 1rw8 (200-500), 4x2j (200-503), 3tzm (200-503), 4x2k (200-503), 4x2n (200-503), 4x0m (200-503), 2wou (200-503), 2wot (200-503), 3gxl (201-503), 3hmm (201-503), 1vjy (201-503), 2l5s (31-115), 1ias (A/B...=162-503), 1b6c (B/D/F/H=162-503), 2pjy (C=33-111), 3kfd (I/J/K/L=31-115)
OPM none
Complexes

TGFB3:TGFR1:TGFR2_HUMAN

TGFR1:TGFR2:TGFB1_HUMAN

Interactions

ACVL1, Complex: ACVL1:TGFR1, PubMed

ACVR1, Complex: TGFR1:ACVR1, PubMed

AMHR2, Complex: TGFR1:AMHR2, PubMed

BAMBI, Complex: BAMBI:TGFR1, PubMed

BMPR2, Complex: TGFR1:BMPR2, PubMed

BMR1B, Complex: TGFR1:BMR1B, PubMed

CD44, Complex: CD44:TGFR1, PubMed

EGLN, Complex: EGLN:TGFR1, PubMed

GOLI, Complex: GOLI:TGFR1, PubMed

ITA5, Complex: TGFR1:ITA5, PubMed

NOTC1, Complex: TGFR1:NOTC1

PREB, Complex: TGFR1:PREB, PubMed

SG196, Complex: SG196:TGFR1, PubMed

STX8, Complex: TGFR1:STX8, PubMed

TGBR3, Complex: TGFR1:TGBR3

TGFR2, Complex: TGFB3:TGFR1:TGFR2, PDBID: 2pjy

Domains

AA: 34-110, PDBID: 2L5S, Subunit A, Seq Identity:100%, Activin types I and II receptor domain

AA: 176-203, PDBID: 1B6C, Subunit B, Seq Identity:100%, Transforming growth factor beta type I GS-motif

AA: 205-492, PDBID: 1B6C, Subunit D, Seq Identity:100%, Protein kinase domain

UniProt annotation for TGFR1_HUMAN » TGF-beta receptor type-1
FUNCTION: Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFBR1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non- canonical, SMAD-independent TGF-beta signaling pathways. For instance, TGFBR1 induces TRAF6 autoubiquitination which in turn results in MAP3K7 ubiquitination and activation to trigger apoptosis. Also regulates epithelial to mesenchymal transition through a SMAD-independent signaling pathway through PARD6A phosphorylation and activation.

CATALYTIC ACTIVITY: ATP + [receptor-protein] = ADP + [receptor- protein] phosphate.

ENZYME REGULATION: Kept in an inactive conformation by FKBP1A preventing receptor activation in absence of ligand. CD109 is another inhibitor of the receptor.

SUBUNIT: Homodimer; in the endoplasmic reticulum but also at the cell membrane. Heterohexamer; TGFB1, TGFB2 and TGFB3 homodimeric ligands assemble a functional receptor composed of two TGFBR1 and TGFBR2 heterodimers to form a ligand-receptor heterohexamer. The respective affinity of TGBRB1 and TGFBR2 for the ligands may modulate the kinetics of assembly of the receptor and may explain the different biological activities of TGFB1, TGFB2 and TGFB3. Interacts with CD109; inhibits TGF-beta receptor activation in keratinocytes. Interacts with RBPMS. Interacts (unphosphorylated) with FKBP1A; prevents TGFBR1 phosphorylation by TGFBR2 and stabilizes it in the inactive conformation. Interacts with SMAD2, SMAD3 and ZFYVE9; ZFYVE9 recruits SMAD2 and SMAD3 to the TGF-beta receptor. Interacts with TRAF6 and MAP3K7; induces MAP3K7 activation by TRAF6. Interacts with PARD6A; involved in TGF-beta induced epithelial to mesenchymal transition. Interacts with SMAD7, NEDD4L, SMURF1 and SMURF2; SMAD7 recruits NEDD4L, SMURF1 and SMURF2 to the TGF-beta receptor. Interacts with USP15 and VPS39.

TISSUE SPECIFICITY: Found in all tissues examined, most abundant in placenta and least abundant in brain and heart.

DISEASE: Loeys-Dietz syndrome 1 (LDS1) OMIM: An aortic aneurysm syndrome with widespread systemic involvement, characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. Some patients have craniosynostosis, exotropy, micrognathia and retrognathia, structural brain abnormalities, and intellectual deficit. mutations affecting the gene represented in this entry. TGFBR1 mutation Gln-487 has been reported to be associated with thoracic aortic aneurysms and dissection (TAAD) (PubMed). This phenotype, also known as thoracic aortic aneurysms type 5 (AAT5), is distinguised from LDS1 by having aneurysms restricted to thoracic aorta. It is unclear, however, if this condition is fulfilled in individuals bearing Gln-487 mutation, that is why they are considered as LDS1 by the OMIM resource.

DISEASE: Multiple self-healing squamous epithelioma (MSSE) OMIM: A disorder characterized by multiple skin tumors that undergo spontaneous regression. Tumors appear most often on sun-exposed regions, are locally invasive, and undergo spontaneous resolution over a period of months leaving pitted scars. mutations affecting the gene represented in this entry.

UniProt features for TGFR1_HUMAN » TGF-beta receptor type-1
SIGNAL 1 33
CHAIN 34 503 TGF-beta receptor type-1.
DOMAIN 175 204 GS.
DOMAIN 205 495 Protein kinase.
MOTIF 193 194 FKBP1A-binding.
ACT_SITE 333 333 Proton acceptor (By similarity).
DISULFID 36 54
DISULFID 38 41
DISULFID 48 71
DISULFID 86 100
DISULFID 101 106
CROSSLNK 391 391 Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) (By similarity).
Amino Acid Sequence for TGFR1_HUMAN » TGF-beta receptor type-1
MEAAVAAPRP RLLLLVLAAA AAAAAALLPG ATALQCFCHL CTKDNFTCVT DGLCFVSVTE TTDKVIHNSM CIAEIDLIPR DRPFVCAPSS KTGSVTTTYC CNQDHCNKIE LPTTVKSSPG LGPVELAAVI AGPVCFVCIS LMLMVYICHN RTVIHHRVPN EEDPSLDRPF ISEGTTLKDL IYDMTTSGSG SGLPLLVQRT IARTIVLQES IGKGRFGEVW RGKWRGEEVA VKIFSSREER SWFREAEIYQ TVMLRHENIL GFIAADNKDN GTWTQLWLVS DYHEHGSLFD YLNRYTVTVE GMIKLALSTA SGLAHLHMEI VGTQGKPAIA HRDLKSKNIL VKKNGTCCIA DLGLAVRHDS ATDTIDIAPN HRVGTKRYMA PEVLDDSINM KHFESFKRAD IYAMGLVFWE IARRCSIGGI HEDYQLPYYD LVPSDPSVEE MRKVVCEQKL RPNIPNRWQS CEALRVMAKI MRECWYANGA ARLTALRIKK TLSQLSQQEG IKM