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- Title
The Mechanism of p53 Rescue by SUSP4.
- Authors
Kim, Do-Hyoung; Lee, Chewook; Lee, Si-Hyung; Kim, Kyung-Tae; Han, Joan J.; Cha, Eun-Ji; Lim, Ji-Eun; Cho, Ye-Jin; Hong, Seung-Hee; Han, Kyou-Hoon
- Abstract
p53 is an important tumor-suppressor protein deactivation of which by mdm2 results in cancers. A SUMO-specific protease 4 (SUSP4) was shown to rescue p53 from mdm2-mediated deactivation, but the mechanism is unknown. The discovery by NMR spectroscopy of a 'p53 rescue motif' in SUSP4 that disrupts p53-mdm2 binding is presented. This 29-residue motif is pre-populated with two transient helices connected by a hydrophobic linker. The helix at the C-terminus binds to the well-known p53-binding pocket in mdm2 whereas the N-terminal helix serves as an affinity enhancer. The hydrophobic linker binds to a previously unidentified hydrophobic crevice in mdm2. Overall, SUSP4 appears to use two synergizing modules, the p53 rescue motif described here and a globular-structured SUMO-binding catalytic domain, to stabilize p53. A p53 rescue motif peptide exhibits an anti-tumor activity in cancer cell lines expressing wild-type p53. A pre-structures motif in the intrinsically disordered proteins is thus important for target recognition.
- Subjects
TUMOR suppressor proteins; SMALL ubiquitin-related modifier proteins; NUCLEAR magnetic resonance spectroscopy; HYDROPHOBIC compounds; HELICES (Algebraic topology)
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 5, p1298
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201607819