Growth hormone receptor structure

The prolactin receptor, PER, which regulates milk production in mammals, belongs to the same receptor class as the growth hormone receptor. In addition to binding the hormone prolactin, PER also binds and is activated by growth hormone. The extracellular domain of PER forms a very stable 1 1 complex with growth hormone in solution this complex has been crystallized and its structure determined (Figure 13.21). We shall compare this structure with the 1 2 complex of the same hormone with GHR. 

Pearce, K.H., Jr., M.H. Ultsch, R.F. Kelley, A.M. de Vos, and J.A. Wells. 1996. Structural and mutational analysis of affinity-inert contact residues at the growth hormone-receptor interface. Biochemistry 35 10300-10307. 

Fig. 11.2. Domain structure of cytokine receptors. Schematic representation of the domain structure of selected cytokine receptors. WS motif conserved WSXWS sequence (W tryptophan S serine X non-conserved amino add) IL interleukin EpoR receptor for erythropoietin GHR growth hormone receptor LIF-R leukemia inhibitory factor receptor G-CSFR granulocyte colony stimulating factor receptor IFNR interferon receptor TNFR tumor necrosis factor receptor NGFR nerve growth factor receptor Fas, CD40 transmembrane receptors of lymphocytes.

Wells, J. A (1995) Structural and functional epitopes in the growth hormone receptor complex. Biotechnology 13,647-651. 

Dimerization is not restricted to receptors. It is a property of many regulatory proteins and enzymes. Homo- and heterodimerization occur in many signal transmitters and transcriptional activators, as we shall see later. Out of many examples of receptor dimerization, I have selected the growth hormone receptor and closely related receptors, because X-ray crystaUographers have provided detailed information on the structural basis of ligand-induced oligomerization. 

Clackson T, Ultsch MH, Wells JA, de Vos AM (1998) Structural and functional analysis of the 1 1 growth hormone receptor complex reveals the molecular basis for receptor affinity. J Mol Biol 277 1111-1128... 

A EXPERIMENTAL FIGURE 13-2 Mutational studies have identified the patches of amino acids in growth hormone and its receptor that determine their highly specific mutual interaction. The outer surface of the plasma membrane is toward the bottom of the figure, and each receptor is anchored to the membrane by a hydrophobic membrane-spanning alpha helix that is not shown. As determined from the three-dimensional structure of the growth hormone-growth hormone receptor complex,... 

Describe how the quaternary structure (monomer-dimer equilibrium) of the human growth hormone receptor changes upon binding human growth hormone. 

All possible combinations of amino acids and interacting geometries were documented to occur in protein structures. The key feature of course, is that the cation must be oriented toward the face of the Phe/Tyr/Trp side chain, not the edge. An especially iinpressive cation-n interaction was first noted by Wilson in the erythropoietin receptor extracellular domain.An interdigitated stack of side chains follows the sequence Lys-Tyr-Arg-Phe-Arg -Trp-Lys, a remarkable string of cation-Ti interactions. Similar motifs are seen in growth hormone receptors and related structures. 

Figure 13.20 Ribbon diagram of the structure of a 1 2 complex between the human growth hormone and the extracellular domains of two receptor molecules. The two receptor molecules (blue) bind the hormone (red) with essentially the same loop regions (yellow).

De Vos, A.M., Ultsch, M., Kossiakoff, A.A. Human growth hormone and extracellular domain of its receptor crystal structure of the complex. Science 255 306-312,... 

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