PXD015279

PXD015279 is an original dataset announced via ProteomeXchange.

Title	Misfolded SOD1 binds the ubiquitin ligase TRAF6
Description	Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1) are the second most common cause of ALS and it is now well accepted that they result in a gain of toxicity due to protein misfolding. We previously demonstrated in the SOD1G93A rat model that misfolded SOD1 exists as distinct conformers and deposits on mitochondrial subpopulations. Here, using SOD1G93A rats coupled with conformation-restricted antibodies for misfolded SOD1 (AMF7-63 and B8H10), we identified the interactomes of the mitochondrial pools of misfolded SOD1. This strategy identified binding partners that uniquely interacted with either AMF7-63- or B8H10-reactive SOD1 conformers as well as a high proportion of interactors common to both conformers. Of this latter set, we identified the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) and determined that exposure of the SOD1 functional loops facilitates this interaction. However, this conformational criterion is not universally fulfilled by all SOD1 mutants and differentiates TRAF6-interacting from non-interacting SOD1 mutants. Functionally, TRAF6 stimulates mutant SOD1 polyubiquitination and aggregation. While TRAF6 E3 ubiquitin ligase activity is required for the former, it is dispensable for the latter, indicating that the polyubiquitination and aggregation of mutant SOD1 mediated by TRAF6 are independent events. We propose that misfolded SOD1 binding to TRAF6 may be relevant to ALS disease.
HostingRepository	PRIDE
AnnounceDate	2020-02-24
AnnouncementXML	Submission_2020-02-23_23:32:03.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD015279
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Arsalan Haqqani
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ

Revision	Datetime	Status	ChangeLog Entry
0	2019-09-02 01:19:54	ID requested
⏵ 1	2020-02-23 23:32:05	announced

Semmler S, Gagn, é M, Garg P, Pickles SR, Baudouin C, Hamon-Keromen E, Destroismaisons L, Khalfallah Y, Chaineau M, Caron E, Bayne AN, Trempe JF, Cashman NR, Star AT, Haqqani AS, Durcan TM, Meiering EM, Robertson J, Grandvaux N, Plotkin SS, McBride HM, Vande Velde C, TNF receptor-associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation. J Biol Chem, 295(12):3808-3825(2020) [pubmed]

submitter keyword: amyotrophic lateral sclerosis (ALS), superoxide dismutase 1 (SOD1), protein misfolding, mitochondria, TNF receptor-associated factor 6 (TRAF6), ubiquitin, aggregation

Arsalan Haqqani
contact affiliation	National Research Council Ottawa, Canada
contact email	arsalan.haqqani@nrc-cnrc.gc.ca
lab head
Arsalan Haqqani
contact affiliation	National Research Council of Canada
contact email	arsalan.haqqani@nrc-cnrc.gc.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015279
     1. Label: PRIDE project
     2. Name: Misfolded SOD1 binds the ubiquitin ligase TRAF6