Growth hormone receptor

The cytokine family of receptors

The GH receptor (GHR) is one of several members of the cytokine superfamily of receptors, also referred to as hematopoietin receptors. There are over 200 protein members of the family currently in the InterPro database. Cytokine receptors are found on various cell types and are generally involved in cell growth and differentiation. Other family members include receptors for thrombopoietin, erythropoietin, prolactin, leptin, interleukins, interferon a, b and g, granulocyte stimulating factor, and ciliary neurotrophic factor. These receptors share the same three-domain architecture, however most of the sequence homology between them is in the extracellular domain responsible for ligand binding, which structurally resembles the Ig-like fibronectin type III (Fn3) domain found in a wide variety of protein families. Specific functions have been mapped to short sequences within individual Fn3 domains. The GHR contains two non-identical Fn3 domains. The intracellular domain of cytokine receptors are not homologous, although they do contain a small conserved proline-rich motif, termed ‘box 1’, required for tyrosine kinase binding.

P10912 Human growth hormone receptor entry from InterPro

Interpro Entry	Method accession	Graphical match	Method name
IPR002996	PS50301		CR1A
IPR003528	PS01352		HEMATOPO_REC_L_F1
IPR003961	PF00041		fn3
IPR003961	SM00060		fn3
IPR008957	SSF49265		FN_III-like
Classification	Domain ID	Structural Domains
2.60.40.30.2	1axiB1
2.60.40.30.3	1a22B2
b.1.2.1	d1kf9c1
b.1.2.1	d1a22b2
b.1.2.1	d1kf9b2

What InterPro tells us

From the graphical match above, you can see that the signatures in InterPro are divided into four entries for the human GHR (hGHR). These entries give information about the domain architecture of the protein, as well as its family relationships.

Starting with the domain architecture of the hGHR, there are three domains in hGHR: an N-terminal extracellular ligand-binding domain, a short transmembrane domain and a C-terminal intracellular tyrosine kinase-binding domain. Only the extracellular domain is represented in InterPro, because it is the only domain that is well characterised and which represents the cytokine superfamily to which hGHR belongs; the other domains show little sequence conservation between family members. The extracellular domain consists of two non-identical fibronectin type III (Fn3)-like subdomains, both of which are contained in IPR008957, representing the Fn3-like fold, and which has one signature, SSF49265 from the SUPERFAMILY database. Some cytokine receptors only contain one Fn3 domain of the type found in IPR003961, as represented by PF00041 and SM00060 from the PFAM and SMART databases, respectively. The last five entries in the table above are from the structural classification databases CATH and SCOP (the names such as d1kf9c1 are derived from the PDB entry upon which they are based; here PDB entry 1kf9, chain c, region 1). If you follow the links to these databases you will find descriptions of the structural features and classification of the Fn3 domains, as well as links to the corresponding PDB entries: 1axiB1 and d1kf9c1 for information on the N-terminal Fn3 domain; 1a22B2, d1a22b2 and d1kf9b2 for information on the second Fn3 domain.

To look at the family relationships that involve GHR, we need to start with the entry at the top of the table, IPR002996, which has one signature representing the cytokine receptor family, PS50301 from the PROSITE database. This is quite a large family of proteins (over 200), that is the parent of several subfamily members, including the IPR003528 hematopoietin receptor subfamily that contains GHR, and which is represented by one signature, PS01352 from the PROSITE database.

What the structure tells us

The crystallographic structure of the GHR has been determined. A description and visualisation of the structural features of GHR can be found at the PDB. Here you can find out more about the molecular mechanisms of GHR activation and signal transduction.

Next: Table of GH receptor proteins

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