TGF-beta receptor type-1 precursor - Homo sapiens (Human)

Names and origin

Protein names

Recommended name:
    TGF-beta receptor type-1
    EC=2.7.11.30
Alternative name(s):
    Transforming growth factor-beta receptor type I
      Short name=TGF-beta receptor type I
    TGF-beta type I receptor
    TbetaR-I
    TGFR-1
    Serine/threonine-protein kinase receptor R4
      Short name=SKR4
    Activin receptor-like kinase 5
      Short name=ALK-5

Gene names

Name:

TGFBR1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	503 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for TGF-beta.
Catalytic activity	ATP + [receptor-protein] = ADP + [receptor-protein] phosphate.
Cofactor	Magnesium or manganese By similarity.
Subunit structure	Interacts with CD109. The unphosphorylated protein interacts with FKBP1A and is stabilized the inactive conformation. Phosphorylation of the GS region abrogates FKBP1A binding. Interacts with SMAD2 when phosphorylated on several residues in the GS region.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Found in all tissues examined, most abundant in placenta and least abundant in brain and heart.
Post-translational modification	Phosphorylated at basal levels in the absence of ligand binding. Activated by multiple phosphorylation, mainly in the GS region.
Involvement in disease	Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 1A (LDS1A) [MIM:609192]; also known as Furlong syndrome or Loeys-Dietz aortic aneurysm syndrome (LDAS). LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree. Defects in TGFBR1 are the cause of Loeys-Dietz syndrome type 2A (LDS2A) [MIM:608967]. LDS2 is an aortic aneurysm syndrome with widespread systemic involvement. 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, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Defects in TGFBR1 are the cause of aortic aneurysm familial thoracic type 5 (AAT5) [MIM:608967]. Aneurysms and dissections of the aorta usually result from degenerative changes in the aortic wall. Thoracic aortic aneurysms and dissections are primarily associated with a characteristic histologic appearance known as 'medial necrosis' in which there is degeneration and fragmentation of elastic fibers, loss of smooth muscle cells, and an accumulation of basophilic ground substance.
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily. Contains 1 GS domain. Contains 1 protein kinase domain.

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Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Aortic aneurysm Craniosynostosis Disease mutation
Domain	Signal Transmembrane
Ligand	ATP-binding Magnesium Manganese Metal-binding Nucleotide-binding
Molecular function	Kinase Receptor Serine/threonine-protein kinase Transferase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	positive regulation of cell proliferation Inferred from mutant phenotype. Source: HGNC protein amino acid phosphorylation Inferred from direct assay. Source: HGNC regulation of transcription Inferred from direct assay. Source: HGNC transforming growth factor beta receptor complex assembly Ref.1 Traceable author statement. Source: ProtInc
Cellular component	integral to plasma membrane Ref.1 Traceable author statement. Source: ProtInc receptor complex Inferred from direct assay. Source: UniProtKB
Molecular function	ATP binding Inferred from direct assay. Source: HGNC SMAD binding Inferred from direct assay. Source: HGNC magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW manganese ion binding Inferred from electronic annotation. Source: UniProtKB-KW transforming growth factor beta binding Inferred from direct assay. Source: HGNC transforming growth factor beta receptor activity, type I Ref.1 Traceable author statement. Source: ProtInc type II transforming growth factor beta receptor binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Potential

Chain

25 – 503

479

TGF-beta receptor type-1

PRO_0000024423

Regions

Topological domain

25 – 125

101

Extracellular Potential

Transmembrane

126 – 147

22

Potential

Topological domain

148 – 503

356

Cytoplasmic Potential

Domain

175 – 204

30

GS

Domain

205 – 495

291

Protein kinase

Nucleotide binding

211 – 219

9

ATP By similarity

Sites

Active site

333

1

Proton acceptor By similarity

Binding site

232

1

ATP By similarity

Amino acid modifications

Modified residue

185

1

Phosphothreonine

Modified residue

186

1

Phosphothreonine

Modified residue

187

1

Phosphoserine

Modified residue

189

1

Phosphoserine

Modified residue

191

1

Phosphoserine

Glycosylation

45

1

N-linked (GlcNAc...) Potential

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Disulfide bond

Natural variations

Natural variant

24 – 26

3

Missing in allele TGFBR1*6A; could be a tumor susceptibility allele.

VAR_022342

Natural variant

26

1

A → AA in allele TGFBR1*10A; rare polymorphism.

VAR_022343

Natural variant

153

1

V → I

VAR_041412

Natural variant

200

1

T → I in LDS1A.

VAR_022344

Natural variant

232

1

K → E in LDS2A.

VAR_029481

Natural variant

241

1

S → L in LDS1A.

VAR_029482

Natural variant

267

1

N → H in a patient with Marfan syndrome.

VAR_029483

Natural variant

291

1

Y → C

VAR_041413

Natural variant

318

1

M → R in LDS1A.

VAR_022345

Natural variant

400

1

D → G in LDS1A.

VAR_022346

Natural variant

487

1

R → P in LDS1A and LDS2A.

VAR_022347

Natural variant

487

1

R → Q in LDS2A and AAT5.

VAR_029484

Natural variant

487

1

R → W in LDS2A.

VAR_029485

Experimental info

Mutagenesis

185 – 186

2

TT → VV: Loss of phosphorylation on threonine residues. Loss of threonine phosphorylation, reduced phosphorylation on serine residues and loss of response to TGF-beta; when associated with A-187; A-189 and A-191

Mutagenesis

187

1

S → A: Loss of threonine phosphorylation, reduced phosphorylation on serine residues and loss of response to TGF-beta; when associated with 185-VV-186; A-189 and A-191

Mutagenesis

189

1

S → A: Loss of threonine phosphorylation, reduced phosphorylation on serine residues and loss of response to TGF-beta; when associated with 185-VV-186; A-187 and A-191

Mutagenesis

191

1

S → A: Loss of threonine phosphorylation, reduced phosphorylation on serine residues and loss of response to TGF-beta; when associated with 185-VV-186; A-187 and A-189

Mutagenesis

200

1

T → D: Loss of response to TGF-beta

Mutagenesis

200

1

T → V: Loss of phosphorylation. Loss of response to TGF-beta

Mutagenesis

204

1

T → D: Constitutive activation

Mutagenesis

204

1

T → V: Reduced phosphorylation. Reduced response to TGF-beta

Secondary structure

1

.

503

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P36897-1 [UniParc].

Last modified June 1, 1994. Version 1.
Checksum: 179F11404725DDCB
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FASTA

503

55,960

        10         20         30         40         50         60 
MEAAVAAPRP RLLLLVLAAA AAAAAALLPG ATALQCFCHL CTKDNFTCVT DGLCFVSVTE 

        70         80         90        100        110        120 
TTDKVIHNSM CIAEIDLIPR DRPFVCAPSS KTGSVTTTYC CNQDHCNKIE LPTTVKSSPG 

       130        140        150        160        170        180 
LGPVELAAVI AGPVCFVCIS LMLMVYICHN RTVIHHRVPN EEDPSLDRPF ISEGTTLKDL 

       190        200        210        220        230        240 
IYDMTTSGSG SGLPLLVQRT IARTIVLQES IGKGRFGEVW RGKWRGEEVA VKIFSSREER 

       250        260        270        280        290        300 
SWFREAEIYQ TVMLRHENIL GFIAADNKDN GTWTQLWLVS DYHEHGSLFD YLNRYTVTVE 

       310        320        330        340        350        360 
GMIKLALSTA SGLAHLHMEI VGTQGKPAIA HRDLKSKNIL VKKNGTCCIA DLGLAVRHDS 

       370        380        390        400        410        420 
ATDTIDIAPN HRVGTKRYMA PEVLDDSINM KHFESFKRAD IYAMGLVFWE IARRCSIGGI 

       430        440        450        460        470        480 
HEDYQLPYYD LVPSDPSVEE MRKVVCEQKL RPNIPNRWQS CEALRVMAKI MRECWYANGA 

       490        500 
ARLTALRIKK TLSQLSQQEG IKM

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References

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[1]	"Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor." Franzen P., ten Dijke P., Ichijo H., Yamashita H., Schulz P., Heldin C.-H., Miyazono K. Cell 75:681-692(1993) [PubMed: 8242743] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning and genomic organization of the human transforming growth factor-beta type I receptor gene." Vellucci V.F., Reiss M. Genomics 46:278-283(1997) [PubMed: 9417915] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"The genomic structure of the gene encoding the human transforming growth factor beta type I receptor." Lynch M.A., Song H., DeGroff V.L., Alam K.Y., Adams E.M., Weghorst C.M. Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Livingston R.J., Rieder M.J., Chung M.-W., Ritchie T.K., Olson A.N., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D., Schackwitz W.S., Sherwood J.K., Sherwood A.M., Leithauser B.J., Nickerson D.A. Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex." Wieser R., Wrana J.L.,

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Secondary structure

Sequences

References