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Reviewed, UniProtKB/Swiss-Prot P10912 (GHR_HUMAN)

Last modified November 25, 2008. Version 113. Feed History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Growth hormone receptor
      Short name=GH receptor
Alternative name(s):
    Somatotropin receptor
Cleaved into the following chain:
    1- Recommended name:
            Growth hormone-binding protein
                Short name=GH-binding protein
                Short name=GHBP
        Alternative name(s):
            Serum-binding protein
Gene names
Name: GHR
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length638 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway By similarity.

The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.

Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.

Subunit structure

On growth hormone (GH) binding, forms homodimers and binds JAK2 via a box 1-containing domain By similarity. Binding to SOCS3 inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5 activation By similarity. Interacts with ADAM17 By similarity.

Subcellular location

Cell membrane; Single-pass type I membrane protein. Note= On growth hormone binding, GHR is ubiquitinated, internalized, down-regulated and transported into a degradative or non-degradative pathway By similarity.

Isoform 2: Cell membrane; Single-pass type I membrane protein. Note= Remains fixed to the cell membrane and is not internalized.

Growth hormone-binding protein: Secreted.

Tissue specificity

Expressed in various tissues with high expression in liver and skeletal muscle. Isoform 4 is predominantly expressed in kidney, bladder, adrenal gland and brain stem. In the placenta, isoform 1 predominantly expressed in chorion and decidua, isoform 4 highly expressed in villi. Isoform 2 is expressed in lung, stomach and muscle. Low levels in liver.

Domain

The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

The box 1 motif is required for JAK interaction and/or activation.

The extracellular domain is the ligand-binding domain representing the growth hormone-binding protein (GHBP).

The ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.

Post-translational modification

The soluble form (GHBP) is produced by phorbol ester-promoted proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE. Shedding is inhibited by growth hormone (GH) binding to the receptor probably due to a conformational change in GHR rendering the receptor inaccessible to ADAM17 By similarity.

On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2 By similarity.

On ligand binding, ubiquitinated on lysine residues in the cytoplasmic domain. This ubiquitination is not sufficient for GHR internalization By similarity.

Polymorphism

Genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia [MIM:143890] patients carrying a mutation in the LDLR gene.

Involvement in disease

Defects in GHR are a cause of Laron dwarfism [MIM:262500]; also known as pituitary dwarfism II; Laron-type pituitary dwarfism I (LTD1) or Laron syndrome (LS). It is the most severe form of growth hormone insensitivity (GHI) characterized by growth impairment, dysmorphic facial features and truncal obesity. Levels of GHBP are low or undetectable in patients with Laron syndrome.

Defects in GHR may be a cause of short stature [MIM:604271]. Short stature is defined by a subnormal rate of growth.

Sequence similarities

Belongs to the type I cytokine receptor family. Type 1 subfamily.

Contains 1 fibronectin type-III domain.

Ontologies

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P10912-1)

Also known as: GHRfl;

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: P10912-2)

Also known as: GHRtr; GHR1-279;

The sequence of this isoform differs from the canonical sequence as follows:
     292-297: RIKMLI → SSSSKD
     298-638: Missing.
Notes: Remains fixed to the cell membrane and is not internalized.
Isoform 3 (identifier: P10912-3)

Also known as: GHR1-277;

The sequence of this isoform differs from the canonical sequence as follows:
     292-294: RIK → KEN
     295-638: Missing.
Isoform 4 (identifier: P10912-4)

Also known as: GHRd3;

The sequence of this isoform differs from the canonical sequence as follows:
     24-24: A → D
     25-46: Missing.
Notes: Arises by species-specific retrovirus-mediated alternative splice mimicry.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1818 Potential
Chain19 – 638620Growth hormone receptor
PRO_0000010957
Chain19 – ?Growth hormone-binding proteinPRO_0000010958

Regions

Topological domain19 – 264246Extracellular Potential
Transmembrane265 – 28824 Potential
Topological domain289 – 638350Cytoplasmic Potential
Domain149 – 251103Fibronectin type-III
Region260 – 2623Required for ADAM17-mediated proteolysis By similarity
Motif240 – 2445WSXWS motif
Motif297 – 3059Box 1 motif
Motif340 – 34910UbE motif

Sites

Site3451Required for endocytosis and down-regulation By similarity

Amino acid modifications

Glycosylation461N-linked (GlcNAc...) Potential
Glycosylation1151N-linked (GlcNAc...) Potential
Glycosylation1561N-linked (GlcNAc...) Potential
Glycosylation1611N-linked (GlcNAc...) Potential
Glycosylation2001N-linked (GlcNAc...) Potential
Disulfide bond56 ↔ 66
Disulfide bond101 ↔ 112
Disulfide bond126 ↔ 140

Natural variations

Alternative sequence241A → D in isoform 4.
VSP_010225
Alternative sequence25 – 4622Missing in isoform 4.
VSP_010226
Alternative sequence292 – 2976RIKMLI → SSSSKD in isoform 2.
VSP_010227
Alternative sequence292 – 2943RIK → KEN in isoform 3.
VSP_010229
Alternative sequence295 – 638344Missing in isoform 3.
VSP_010230
Alternative sequence298 – 638341Missing in isoform 2.
VSP_010228
Natural variant561C → S in Laron dwarfism.
VAR_018426
Natural variant581S → L in Laron dwarfism.
VAR_018427
Natural variant621E → K in short stature; idiopathic autosomal.
VAR_002708
Natural variant681W → R in Laron dwarfism.
VAR_018428
Natural variant891R → K in Laron dwarfism.
VAR_002709
Natural variant1141F → S in Laron dwarfism; loss of ability to bind ligand.
VAR_002710
Natural variant1431V → A in Laron dwarfism.
VAR_002711
Natural variant1491P → Q in Laron dwarfism; disrupts GH binding.
VAR_018429
Natural variant1621V → D in Laron dwarfism.
VAR_002712
Natural variant1621V → F: dbSNP rs6413484.
VAR_020002
Natural variant1621V → I in short stature; idiopathic autosomal.
VAR_018430
Natural variant1701D → H in Laron dwarfism; abolishes receptor homodimerization.
VAR_002713
Natural variant1711I → T in Laron dwarfism; almost completely abolishes GH-binding at cell surface: 53% binding to membrane fractions.
VAR_018431
Natural variant1721Q → P in Laron dwarfism; almost completely abolishes GH-binding at cell surface and in membrane fractions.
VAR_018432
Natural variant1731V → G in Laron dwarfism; almost completely abolishes GH-binding at cell surface: 26% binding to membrane fractions.
VAR_018433
Natural variant1791R → C in Laron dwarfism and short stature; idiopathic autosomal.
VAR_002714
Natural variant1791R → H: dbSNP rs6181.
VAR_013937
Natural variant2261Y → C in Laron dwarfism.
VAR_018434
Natural variant2291R → G in Laron dwarfism.
VAR_002715
Natural variant2291R → H in short stature; idiopathic autosomal. dbSNP rs6177.
VAR_013938
Natural variant2421E → D in short stature; idiopathic autosomal.
VAR_002716
Natural variant2441S → I in Laron dwarfism.
VAR_018435
Natural variant2621D → N in Laron dwarfism.
VAR_018436
Natural variant4401C → F in Laron dwarfism. dbSNP rs6182.
VAR_013939
Natural variant4651E → K: dbSNP rs34283856.
VAR_032704
Natural variant4951P → T: dbSNP rs6183.
VAR_013940
Natural variant5441I → L Polymorphism with a modifier effect on plasma HDL cholesterol levels in familial hypercholesterolemia patients. dbSNP rs6180.
VAR_013941
Natural variant5791P → T: dbSNP rs6184.
VAR_013942

Experimental info

Mutagenesis2601E → A: No change in shedding activity: No change in hormone binding
Mutagenesis2611E → A: No change in shedding activity: No change in hormone binding
Mutagenesis2621D → A: No change in shedding activity: No change in hormone binding

Secondary structure

.............................. 638
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (GHRfl) [UniParc].

Last modified July 1, 1989. Version 1.
Checksum: EAF77EADE4787822

FASTA63871,500
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