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Biophysical and structural insight into the USP8/14‐3‐3 interaction
Author(s) -
Centorrino Federica,
Ballone Alice,
Wolter Madita,
Ottmann Christian
Publication year - 2018
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13017
Subject(s) - isothermal titration calorimetry , deubiquitinating enzyme , ubiquitin , chemistry , epidermal growth factor receptor , microbiology and biotechnology , biology , receptor , biophysics , biochemistry , gene
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 14‐3‐3ζ 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.