Autoinhibitory structure of the WW domain of HYPB/SETD2 regulates its interaction with the proline-rich region of huntingtin.
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.
Mesh Terms:
Amino Acid Sequence, Binding Sites, Histone-Lysine N-Methyltransferase, Humans, Huntingtin Protein, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Peptides, Protein Conformation, Protein Structure, Tertiary
Amino Acid Sequence, Binding Sites, Histone-Lysine N-Methyltransferase, Humans, Huntingtin Protein, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Peptides, Protein Conformation, Protein Structure, Tertiary
Structure
Date: Mar. 04, 2014
PubMed ID: 24412394
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