Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1211-1220 |
| Number of pages | 10 |
| Journal | FEBS Letters |
| Volume | 592 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Apr 2018 |
Keywords
- 14-3-3 proteins
- Fluorescence polarization
- Isothermal titration calorimetry
- Ubiquitin-specific protease 8
- X-ray crystallography
- isothermal titration calorimetry
- fluorescence polarization
- ubiquitin-specific protease 8
- Endopeptidases/chemistry
- Humans
- Pituitary ACTH Hypersecretion/genetics
- Crystallography, X-Ray
- Ubiquitin Thiolesterase/chemistry
- ErbB Receptors/genetics
- Proteolysis
- Protein Structure, Quaternary
- 14-3-3 Proteins/chemistry
- Endosomal Sorting Complexes Required for Transport/chemistry