PXD018831

PXD018831 is an original dataset announced via ProteomeXchange.

Title	The oxidoreductase PYROXD1 links human myopathies with pre-tRNA splicing and the unfolded protein response.
Description	PYROXD1 is a largely unstudied essential flavoprotein, whose variants were recently reported to cause myopathies in humans. Here, we report the first biochemical and structural characterization of PYROXD1 and uncover its function as a protector of the tRNA ligase complex from oxidative inactivation. The tRNA ligase complex is essential for the biogenesis of several tRNAs and for the unfolded protein response in humans, and loses activity in cells depleted of PYROXD1. Our mass spectrometry analysis of immunoprecipitates of FLAG-PYROXD1 revealed the tRNA ligase complex as the main interactor of PYROXD1 in presence of nicotinamide adenine dinucleotides, NAD(P)(H). Upon binding to the tRNA ligase complex loaded with NAD(P)H, which sensitizes it to oxidative inactivation, PYROXD1 locally converts the dinucleotide to the protective, oxidized form, NAD(P)+. This function is impaired in disease-causing variants N155S and Q372H, thus establishing the tRNA ligase complex as a potential key player in PYROXD1-related myopathies.
HostingRepository	PRIDE
AnnounceDate	2021-06-24
AnnouncementXML	Submission_2021-06-24_07:04:18.472.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dorothea Anrather
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-27 06:27:03	ID requested
⏵ 1	2021-06-24 07:04:19	announced

Asanovi, ć I, Strandback E, Kroupova A, Pasajlic D, Meinhart A, Tsung-Pin P, Djokovic N, Anrather D, Schuetz T, Suskiewicz MJ, Sillamaa S, K, ö, cher T, Beveridge R, Nikolic K, Schleiffer A, Jinek M, Hartl M, Clausen T, Penninger J, Macheroux P, Weitzer S, Martinez J, as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response. Mol Cell, 81(12):2520-2532.e16(2021) [pubmed]

submitter keyword: Human, LC-MS/MS, flavoprotein, immunoprecipitation

Javier Martinez
contact affiliation	Center for Medical Biochemistry, Max Perutz Labs, Medical University of Vienna, Vienna BioCenter(VBC), Austria
contact email	Javier.martinez@meduniwien.ac.at
lab head
Dorothea Anrather
contact affiliation	Max Perutz Laboratories
contact email	dorothea.anrather@univie.ac.at
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018831
     1. Label: PRIDE project
     2. Name: The oxidoreductase PYROXD1 links human myopathies with pre-tRNA splicing and the unfolded protein response.