PXD011840

PXD011840 is an original dataset announced via ProteomeXchange.

Title	Structural and functional characterization of ubiquitin variant inhibitors of USP15
Description	The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. Taking advantage of the modular nature of ubiquitin, we designed a linear dimer (diUbV) consisting of a UbV that bound the DUSP domain followed by a UbV that bound the catalytic domain, which exhibited enhanced specificity and more potent inhibition of USP15 catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the TGF- pathway. Structural analyses of three distinct UbVs bound to the catalytic domain revealed that the inhibitors locked the active site in a closed, inactive conformation. The structure of a UbV-DUSP domain complex revealed that the UbV formed an unusual strand-swapped dimer that bound two DUSP domains. These inhibitors will enable the study of USP15 function in vitro and in vivo to explore the role of the enzyme in oncology, neurology, immunology and inflammation.
HostingRepository	PRIDE
AnnounceDate	2019-01-16
AnnouncementXML	Submission_2019-05-27_03:28:03.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD011840
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Jonathan Krieger
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Deamidated; Oxidation; Carbamidomethyl
Instrument	Q Exactive; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2018-11-27 02:04:29	ID requested
1	2019-01-16 07:07:48	announced
⏵ 2	2019-05-27 03:28:04	announced	Updated publication reference for PubMed record(s): 30713027.

Teyra J, Singer AU, Schmitges FW, Jaynes P, Kit Leng Lui S, Polyak MJ, Fodil N, Krieger JR, Tong J, Schwerdtfeger C, Brasher BB, Ceccarelli DFJ, Moffat J, Sicheri F, Moran MF, Gros P, Eichhorn PJA, Lenter M, Boehmelt G, Sidhu SS, Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15. Structure, 27(4):590-605.e5(2019) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: USP15

Sachdev S. Sidhu
contact affiliation	The Donnelly Centre, University of Toronto, Toronto, ON, Canada M5S 3E1 & Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8
contact email	sachdev.sidhu@utoronto.ca
lab head
Jonathan Krieger
contact affiliation	SickKids/University of Toronto
contact email	Jonathan.krieger@sickkids.ca
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/2019/01/PXD011840

PRIDE project URI

• PRIDE
  1. PXD011840
     1. Label: PRIDE project
     2. Name: Structural and functional characterization of ubiquitin variant inhibitors of USP15