The Mechanism of p53 Rescue by SUSP4

Abstract

p53 is an important tumor-suppressor protein deactivation of which by mdm2 results in cancers.ASUMOspecific protease 4( SUSP4) was shown to rescue p53 from mdm2-mediated deactivation, but the mechanism is unknown. The discovery by NMR spectroscopyofa"p53 rescue motif"in SUSP4 that disrupts p53-mdm2 binding is presented. This 29residue motif is pre-populated with two transient helices connected by ahydrophobic 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.T he hydrophobic linker binds to ap reviously unidentified hydrophobic crevice in mdm2. Overall, SUSP4 appears to use two synergizing modules,t he p53 rescue motif described here and ag lobular-structured SUMO-binding catalytic domain, to stabilizep 53. Ap 53 rescue motif peptide exhibits an antitumor activity in cancer cell lines expressing wild-type p53. A pre-structures motif in the intrinsically disordered proteins is thus important for target recognition.

Targeting SUMO Signaling to Wrestle Cancer

“…SENPs can counteract MDM2 SUMOylation. UV radiation induces SUSP4, a mouse SUMO protease that removes SUMO from MDM2, leading to stabilization of p53 [47,48]. Lastly, RPL11 a regulator protein of the MDM2-p53 axis is also SUMOylated and potentially suppresses MDM2, via a currently unknown mechanism [49].…”

Thermal Decomposition Properties of Gamma-Irradiated Polyvinyl Alcohol (PVA)/Methyl Cellulose (MC) Blends

“…The conversion of some of the hydroxyl groups of cellulose into hydrophobic groups attenuates the hydrogen bonding, thus decreasing the crystallinity and increasing the water solubility. Since MC is a polyhydroxy polymer, it can be chemically crosslinked with a dialdehyde in the presence of a strong acid to produce hydrogels [12][13][14][15][16][17]. So far, little was known about the structure of the chemically crosslinked MC hydrogels.…”