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Delineation of functional subdomains of Huntingtin protein and their interaction with HAP40

  1. Author:
    Alteen, Matthew G
    Deme,Justin
    Alvarez, Claudia P
    Loppnau, Peter
    Hutchinson, Ashley
    Seitova, Alma
    Chandrasekaran, Renu
    Silva Ramos, Eduardo
    Secker, Christopher
    Alqazzaz, Mona
    Wanker, Erich E
    Lea, Susan M
    Arrowsmith, Cheryl H
    Harding, Rachel J

  2. Author Address

    Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; POINT Biopharma, 22 St Clair Avenue E Suite 1201, Toronto, ON M4T 2S3, Canada., Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; SCIEX, 71 Four Valley Dr, Vaughan, ON L4K 4V8, Canada., Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada., Neuroproteomics, Max Delbr 252;ck Center for Molecular Medicine, Robert-R 246;ssle-Str. 10, 13125 Berlin, Germany., Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: cheryl.arrowsmith@uhnresearch.ca., Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: rachel.harding@utoronto.ca.,
    1. Year: 2023
    2. Date: Sep 7
    3. Epub Date: 2023 06 20
  2. Journal: Structure (London, England : 1993)
    1. 31
  4. Type of Article: Article
  1. Abstract:

    The huntingtin (HTT) protein plays critical roles in numerous cellular pathways by functioning as a scaffold for its many interaction partners and HTT knock out is embryonic lethal. Interrogation of HTT function is complicated by the large size of this protein so we studied a suite of structure-rationalized subdomains to investigate the structure-function relationships within the HTT-HAP40 complex. Protein samples derived from the subdomain constructs were validated using biophysical methods and cryo-electron microscopy, revealing they are natively folded and can complex with validated binding partner, HAP40. Derivatized versions of these constructs enable protein-protein interaction assays in vitro, with biotin tags, and in cells, with luciferase two-hybrid assay-based tags, which we use in proof-of-principle analyses to further interrogate the HTT-HAP40 interaction. These open-source biochemical tools enable studies of fundamental HTT biochemistry and biology, will aid the discovery of macromolecular or small-molecule binding partners and help map interaction sites across this large protein. Copyright © 2023 Elsevier Ltd. All rights reserved.

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External Sources

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  2. DOI: 10.1016/j.str.2023.06.002
  3. PMID: 37390814
  4. PII : S0969-2126(23)00198-3

Library Notes

  1. Fiscal Year: FY2022-2023
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