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  The cryo-electron microscopy structure of huntingtin

Guo, Q., Huang, B., Cheng, J., Seefelder, M., Engler, T., Pfeifer, G., et al. (2018). The cryo-electron microscopy structure of huntingtin. Nature, 555(7694), 117-120. doi:10.1038/nature25502.

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 Creators:
Guo, Qiang1, Author              
Huang, Bin2, Author
Cheng, Jingdong2, Author
Seefelder, Manuel2, Author
Engler, Tatjana2, Author
Pfeifer, Günter1, Author              
Oeckl, Patrick2, Author
Otto, Markus2, Author
Moser, Franziska2, Author
Maurer, Melanie2, Author
Pautsch, Alexander2, Author
Baumeister, Wolfgang1, Author              
Fernandez-Busnadiego, Ruben1, Author              
Kochanek, Stefan2, Author
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              
2external, ou_persistent22              

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Free keywords: EM STRUCTURE DETERMINATION; HEAT REPEATS; PROTEIN; TOXICITY; DISEASE; FRAGMENTS; CLEAVAGE; PHOSPHORYLATION; STABILITY; COMPLEXScience & Technology - Other Topics;
 Abstract: Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription(1,2). Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub(1,3,4). Furthermore, Huntington's disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT5,6. However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans)(7) to an overall resolution of 4 angstrom. HTT is largely a-helical and consists of three major domains. The amino-and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely alpha-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. These data rationalize previous biochemical results and pave the way for improved understanding of the diverse cellular functions of HTT.

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Language(s): eng - English
 Dates: 2018-02-212018-03
 Publication Status: Published in print
 Pages: 17
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000426247600043
DOI: 10.1038/nature25502
 Degree: -

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Project name : GA ERC-2012-SyG_318987–ToPAG
Grant ID : 318987
Funding program : Funding Programme 7 (FP7)
Funding organization : European Commission (EC)

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 555 (7694) Sequence Number: - Start / End Page: 117 - 120 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238