Autoinhibitory structure of the WW domain of HYPB/SETD2 regulates its interaction with the proline-rich region of huntingtin

Yong Guang Gao, Hui Yang, Jian Zhao, Ya Jun Jiang, Hong Yu Hu

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Huntington's disease (HD) is an autosomally dominant neurodegenerative disorder caused by expansion of polyglutamine (polyQ) in the huntingtin (Htt) protein. Htt yeast two-hybrid protein B (HYPB/SETD2), a histone methyltransferase, directly interacts with Htt and is involved in HD pathology. Using NMR techniques, we characterized a polyproline (polyP) stretch at the C terminus of HYPB, which directly interacts with the following WW domain and leads this domain predominantly to be in a closed conformational state. The solution structure shows that the polyP stretch extends from the back and binds to the WW core domain in a typical binding mode. This autoinhibitory structure regulates interaction between the WW domain of HYPB and the proline-rich region (PRR) of Htt, as evidenced by NMR and immunofluorescence techniques. This work provides structural and mechanistic insights into the intramolecular regulation of the WW domain in Htt-interacting partners and will be helpful for understanding the pathology of HD.

Original languageEnglish (US)
Pages (from-to)378-386
Number of pages9
JournalStructure
Volume22
Issue number3
DOIs
StatePublished - Mar 4 2014
Externally publishedYes

Bibliographical note

Funding Information:
The authors would like to thank Dr. Q.H. Huang for providing the cDNA encoding the C-terminal part of HYPB/SETD2 and Meng Wu for technical help in NMR data acquisition. This work was supported by grants from the National Basic Research Program of China (2011CB911104 and 2012CB911003) and the National Natural Science Foundation of China (31200570).

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