The Mechanism of p53 Rescue by SUSP4

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• 作者：Do-Hyoung Kim ; Dr. Chewook Lee ; Dr. Si-Hyung Lee ; Prof. Kyung-Tae Kim ; Joan J. Han ; Eun-Ji Cha ; Ji-Eun Lim ; Ye-Jin Cho ; Prof. Seung-Hee Hong and Dr. Kyou-Hoon Han
• 刊名：Angewandte Chemie International Edition
• 出版年：2017
• 出版时间：January 24, 2017
• 年：2017
• 卷：56
• 期：5
• 页码：1278-1282
• 全文大小：1350K
• ISSN：1521-3773

文摘

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.