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First published online 4 July 2006
doi: 10.1242/jcs.03036

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Disulfide bonds determine growth hormone receptor folding, dimerisation and ligand binding

Department of Cell Biology, Institute of Biomembranes, University Medical Center Utrecht, Heidelberglaan 100, G02.525, 3584 CX Utrecht, The Netherlands

^* Author for correspondence (e-mail: strous{at}med.uu.nl)

Accepted 3 May 2006

The growth hormone receptor contains seven cysteine residues in its extracellular domain. The six in the growth hormone binding domain form disulfide bonds, and help the receptor to gain its correct three-dimensional structure. In this study we replaced the cysteine for serine and alanine residues and investigated their role in growth hormone receptor folding, dimerisation and signal transduction. Folding and growth hormone binding capacity of the wild-type growth hormone receptor require less than two minutes for completion. Although less efficient, all mutant receptors arrive at the cell surface as pre-formed dimers. Disulfide bond C38-C48 is important for efficient maturation. The middle disulfide-bond, C83-C94, is important for ligand binding. Removing disulfide bond C108-C122 has little effect without affecting signalling. When two or all disulfide bonds are changed, ligand binding and activation are blocked. Dimerisation is delayed when all disulfide bonds are destroyed.

Key words: Growth hormone, Cytokine receptor, Folding, Dimerisation, ER, Disulfide bonds

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