Journal
FEBS LETTERS
Volume 592, Issue 7, Pages 1211-1220Publisher
WILEY
DOI: 10.1002/1873-3468.13017
Keywords
14-3-3 proteins; fluorescence polarization; isothermal titration calorimetry; ubiquitin-specific protease 8; X-ray crystallography
Funding
- H Marie Curie Actions of the European Commission through the TASPPI project [675179]
- Marie Curie Actions (MSCA) [675179] Funding Source: Marie Curie Actions (MSCA)
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The ubiquitin-specific protease 8 (USP8)/14-3-3 protein-protein interaction has recently been shown to exert a significant role in the pathogenesis of Cushing's disease (CD). USP8 is a deubiquitinase that prevents epidermal growth factor receptor (EGFR) degradation. Impairment of 14-3-3 binding leads to a higher deubiquitination of EGFR and results in a higher EGFR signaling and an increased production of adrenocorticotropic hormone. Here we report the high-resolution crystal structure of the 14-3-3 binding motif of USP8 surrounding Ser718 in complex with 14-3-3 zeta and characterize the interaction with fluorescence polarization and isothermal titration calorimetry. Furthermore, we analyze the effect of USP8 mutations identified in CD on binding to 14-3-3.
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