PXD013786

PXD013786 is an original dataset announced via ProteomeXchange.

Title	Paradoxical mitotic exit induced by a small molecule inhibitor of APC/C Cdc20
Description	The Anaphase Promoting Complex/Cyclosome (APC/C) is a mega-dalton ubiquitin ligase that initiates mitotic exit by targeting substrates for degradation. The APC/C is activated by Cdc20, which acts as a substrate receptor, and is inhibited by the mitotic checkpoint complex (MCC), which delays mitotic exit when the spindle assembly checkpoint (SAC) is activated. We previously identified apcin, a small molecule ligand of Cdc20, as an inhibitor of APC/CCdc20. Surprisingly, we found that apcin paradoxically accelerates substrate degradation and promotes mitotic exit in cells with high SAC activity. Biochemical studies indicate that apcin cooperates with p31comet to relieve MCC-dependent inhibition of APC/C. Apcin’s behavior as an antagonist of Cdc20 can thus result in either net inhibition of APC/C, delaying mitotic exit when SAC activity is slow, or net activation of APC/C, promoting mitotic exit when SAC activity is high. Genetic experiments suggest that the dual behaviors of apcin arise from targeting a common binding site in Cdc20 that is required for both substrate ubiquitination as well as efficient APC/C inhibition by MCC. We therefore establish a new mechanism through which a small molecule, by targeting a single site on a dynamic protein interface, can lead to opposing biological effects depending on the regulatory context.
HostingRepository	PRIDE
AnnounceDate	2020-01-07
AnnouncementXML	Submission_2020-03-24_00:32:52.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joao Paulo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-09 06:44:58	ID requested
1	2020-01-07 04:59:36	announced
⏵ 2	2020-03-24 00:32:53	announced	2020-03-24: Updated publication reference for PubMed record(s): 32152539.

Richeson KV, Bodrug T, Sackton KL, Yamaguchi M, Paulo JA, Gygi SP, Schulman BA, Brown NG, King RW, . Nat Chem Biol, 16(5):546-555(2020) [pubmed]

submitter keyword: CDC20, mitosis, Apcin

Joao A. Paulo
contact affiliation	Cell Biology, Harvard Medical School
contact email	joao_paulo@hms.harvard.edu
lab head
Joao Paulo
contact affiliation	Harvard Medical School
contact email	joao_paulo@post.harvard.edu
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/2020/01/PXD013786

PRIDE project URI

• PRIDE
  1. PXD013786
     1. Label: PRIDE project
     2. Name: Paradoxical mitotic exit induced by a small molecule inhibitor of APC/C Cdc20