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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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Genre: Zeitschriftenartikel

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

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Schlagwörter: EM STRUCTURE DETERMINATION; HEAT REPEATS; PROTEIN; TOXICITY; DISEASE; FRAGMENTS; CLEAVAGE; PHOSPHORYLATION; STABILITY; COMPLEXScience & Technology - Other Topics;
 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2018-02-212018-03
 Publikationsstatus: Erschienen
 Seiten: 17
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: ISI: 000426247600043
DOI: 10.1038/nature25502
 Art des Abschluß: -

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Projektname : GA ERC-2012-SyG_318987–ToPAG
Grant ID : 318987
Förderprogramm : Funding Programme 7 (FP7)
Förderorganisation : European Commission (EC)

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Titel: Nature
  Kurztitel : Nature
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: London : Nature Publishing Group
Seiten: - Band / Heft: 555 (7694) Artikelnummer: - Start- / Endseite: 117 - 120 Identifikator: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238