PXD006792

PXD006792 is an original dataset announced via ProteomeXchange.

Title	Tadpole-like conformations of polyglutamine-expanded soluble huntingtin exon 1 engenders novel interactions
Description	Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington’s disease. To understand the structural basis of this toxicity, we characterized the structure of monomeric Httex1 for two polyQ lengths using hydrogen-deuterium exchange and nuclear magnetic resonance experiments. NMR analysis of Httex1 with polyQ length of 25 glutamines showed the presence of helical structure in the N-terminal region which continued into the polyQ tract. Within these regions the 15N{1H} NOE averages about 0.4, consistent with a protein that lacks structure, but also consistent with Httex1 being not fully disordered. However, both NMR and mass spectrometry hydrogen-deuterium exchange experiments showed no protection suggesting a lack of any stabilizing hydrogen bonds. Atomistic simulations showed that these seemingly conflicting features originated from tadpole-like topologies composed of a globular head that included the N-terminal amphipathic region adsorbed on a collapsed polyQ domain and a semi-flexible C-terminal proline-rich region tail. The surface area of the disordered globular domain increased with polyQ length to promote gain-of-function interactions with a range of proteins in a mouse neuroblastoma cell model, which included the stress granule protein Fus. Overexpression of Fus potently reduced toxicity in cells with soluble, polyQ-expanded Httex1. These results collectively suggested that the tadpole-like structure of Httex1 stimulates novel gain-of-function interactions that can be harmful to cell viability and can be sequestered competitively by interactions with other proteins sharing similar low complexity structures such as Fus.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:39:03.218.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Estella Newcombe
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-06-23 03:55:03	ID requested
1	2019-11-11 00:32:32	announced
⏵ 2	2024-10-22 04:39:04	announced	2024-10-22: Updated project metadata.

10.1016/j.jmb.2018.03.031;

Newcombe EA, Ruff KM, Sethi A, Ormsby AR, Ramdzan YM, Fox A, Purcell AW, Gooley PR, Pappu RV, Hatters DM, Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length. J Mol Biol, 430(10):1442-1458(2018) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: huntingtin,Huntington's disease, polyq, neurodegeneration

Danny Martin Hatters
contact affiliation	Department of Biochemistry and Molecular Biology, Hatters Lab, University of Melbourne, Australia
contact email	dhatters@unimelb.edu.au
lab head
Estella Newcombe
contact affiliation	University of Melbourne
contact email	estella.newcombe@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/11/PXD006792

PRIDE project URI

• PRIDE
  1. PXD006792
     1. Label: PRIDE project
     2. Name: Tadpole-like conformations of polyglutamine-expanded soluble huntingtin exon 1 engenders novel interactions