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281/42/31638    most recent
M604770200v1
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Papers In Press, published online ahead of print August 9, 2006
J. Biol. Chem, 10.1074/jbc.M604770200
Submitted on May 18, 2006
Accepted on August 9, 2006

Significance of ectodomain cysteine-boxes 2 and 3 for the activation mechanism of the thyroid stimulating hormone receptor

Sandra Mueller, Gunnar Kleinau, Holger Jaeschke, Susanne Neumann, Gerd Krause, and Ralf Paschke

Medizinische Klinik und Poliklinik III, Universität Leipzig, Leipzig 04103

Corresponding Author: pasr{at}medizin.uni-leipzig.de

Recently, we identified constitutively activating mutations (CAMs) at positions D403, E404, and N406 in the third extracellular cysteine-box (C-b3) of the thyroid stimulating hormone receptor (TSHR). We hypothesized that this epitope could act as a molecular interface between the extracellular and serpentine domain. In this study we present a model for properties of potential interaction partners for this epitope. Moreover, we show that P400 and P407 adjacent to this epitope are also important for stabilizing the partially active, basal conformation of the wild type TSHR. Furthermore, the mutation K291A in the second extracellular cysteine-box (C-b2) was identified as a new CAM, which releases the basal conformation of the wt receptor like the known tryptic cleavage in its close vicinity. Taken together, we provide an activation scenario at the C-b2/C-b3 unit. Three anchor fragments (anchor I-III) most likely constrain the basal conformation. The three anchor fragments are tightly packed. A disulfide bridge holds the C-b2/C-b3 portions in close positions. Independent of the type of conformational interference - side chain modifications, tryptic cleavage or hormone stimulation - which acts on the constrained C-b2/C-b3 wt conformation, it will always release one of the anchor fragments. Subsequently, this results in a conformational displacement of the C-b2/C-b3 portions relative to each other, inducing receptor activation.


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