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

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.
AuthorsYong-Guang Gao, Hui Yang, Jian Zhao, Ya-Jun Jiang, Hong-Yu Hu
JournalStructure (London, England : 1993) (Structure) Vol. 22 Issue 3 Pg. 378-86 (Mar 04 2014) ISSN: 1878-4186 [Electronic] United States
PMID24412394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Peptides
  • polyproline
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human
Topics
  • Amino Acid Sequence
  • Binding Sites
  • Histone-Lysine N-Methyltransferase (chemistry, genetics, metabolism)
  • Humans
  • Huntingtin Protein
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins (chemistry, metabolism)
  • Peptides
  • Protein Conformation
  • Protein Structure, Tertiary

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