The mechanism of p53 rescue by SUSP4

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Title
The mechanism of p53 rescue by SUSP4
Author(s)
Do-Hyoung Kim; Chewook Lee; Si-Hyung Lee; K T Kim; J J Han; Eun Ji Cha; Ji Eun Lim; Ye-Jin Cho; S H Hong; Kyou Hoon Han
Bibliographic Citation
Angewandte Chemie-International Edition, vol. 56, no. 5, pp. 1278-1282
Publication Year
2017
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
Keyword
intrinsically disordered proteinNMR spectroscopyp53pre-structured motifSUSP4
ISSN
1433-7851
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/anie.201607819
Type
Article
Appears in Collections:
Division of Bio Technology Innovation > Core Facility Management Center > 1. Journal Articles
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