da Silva Almeida AC, Hocking HG, Boelens R, Strous GJ, van Rossum AG

Growth hormone (GH) binding to the GH receptor (GHR) triggers essential signaling pathways that promote growth and metabolic regulation. The sensitivity of the cells to GH is mainly controlled by the endocytosis of the receptor via βTrCP. In this study we show that βTrCP interacts directly via its WD40 domain ...

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with the ubiquitin dependent endocytosis motif (UbE) in GHR, promoting GHR ubiquitination in vitro. NMR experiments demonstrated that the UbE motif is essentially unstructured, and together with functional mapping of the UbE and βTrCP WD40 residues necessary for binding, lead to a unique interaction model of βTrCP with GHR-UbE. This interaction is different from the conventional bTrCP-substrate interactions described to date. Therefore, this interaction represents a promising specific target to develop drugs that inhibit GHR endocytosis and increase GH sensitivity in cachexia patients.

Date: Apr. 22, 2013

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