An Autoinhibitory Structure: Intramolecular Regulation of the WW Domain of HYPB/SETD2 for Interacting with Huntingtin
Source:
Time: 2015-09-20
Huntington’s disease (HD) is a neurodegenerative disorder that affects the nerve cells in the brain causing movement, cognition and behavior problems. Since huntingtin (Htt) was first identified as the mutation responsible for HD in 1993, a large number of studies have been conducted seeking to understand how this defective gene product causes the drastic neurodegeneration in HD patients. However, many important features of the disease are still poorly understood.
A research team led by Prof. HU Hongyu from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences revealed that the interaction between Htt and its partner protein HYPB/SETD2 is intramolecularly regulated by a polyproline (polyP) stretch in HYPB.
They found that the WW domain of HYPB is intramolecularly inhibited by a preceding polyP stretch. Further research revealed that the WW domain contains two conformational states (open and closed) in solution. They solved the solution structures of the WW domain in open and closed states, respectively. The structure of the closed state showed that the canonical binding site of the WW domain with its ligands is covered by the polyP stretch intramolecularly, so the polyP stretch putatively inhibits the interaction between the WW domain of HYPB and the proline-rich region (PRR) of Htt. This hypothesis was then proved by NMR titration and immunofluorescence microscopy imaging. This study uncovered a new regulatory mechanism for the interaction between Htt and HYPB, which will be helpful for elucidation of the HD pathology and identification of drug target for the disease.
This work entitled “
Autoinhibitory Structure of the WW Domain of HYPB/SETD2 Regulates Its Interaction with the Proline-Rich Region of Huntingtin” was published online in
Structure on January 9, 2014. This work was supported by grants from the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Chinese Academy of Sciences.
CONTACT:
HU Hongyu, Principle Investigator
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences Shanghai 200031, China
Phone: 86-21-54921121;
E-mail:
hyhu@sibcb.ac.cn.
Schematic Representation of the Intramolecular Regulation of the WW domain of HYPB interacting with Htt.
The structure of the WW domain in PP2WW of HYPB is in equilibrium between the closed and the open conformational states. This intramolecular polyP interaction with the WW moiety in PP2WW impedes interaction of the oncoming PRR of the Htt protein, which forms aggregates through β-sheet structures by the expanded polyQ tracts. (Image provided by Dr. HU Hongyu’s group)
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