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Department of Cell Biology and Institute of Biomembranes, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
Address all correspondence and requests for reprints to: Ger J. Strous, Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, Room G02.525, 3584 CX Utrecht, The Netherlands. E-mail: strous{at}med.uu.nl.
GH binding to cell surface-localized GH receptors (GHRs) induces a conformational change of the dimerized receptors, resulting in activation of Janus kinase 2 and downstream signaling pathways. Interactions between the extracellular subdomain 2 of adjacent GHR polypeptides result in a 500-Å2 contact interface, which has previously been suggested to stabilize the GH-(GHR)2 complex. In this study, we investigated further the role of subdomain 2 in GHR function. Amino acids that participate in (e.g. aspartic acid 152, tyrosine 200, or serine 201) or lie close to (e.g. asparagine 143 or cysteine 241) the contact interface were mutated in rabbit GHR. Surprisingly, none of the mutations affected GHR dimerization, as demonstrated by coimmunoprecipitation of a truncated, epitope-tagged GHR. However, signal transduction of GHR(D152H), GHR(Y200D), and GHR(S201K) mutants was precluded. More insight into the molecular mechanism of the signaling defect was obtained when we examined the effect of the mutations on the integrity of the GH-(GHR)2 complex in a protease-protection assay. In contrast to wild-type GHR, GHR(N143K), and GHR(C241S), the GHR(D152H), GHR(Y200D), and GHR(S201K) mutants were not protected against protease digestion by GH, indicating that a structural change is prevented. Together, we provide new evidence for a critical role of aspartic acid 152, tyrosine 200, and serine 201 of the GHR contact interface in the GH-induced conformational change to a signaling-competent complex rather than in GHR dimerization.
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