PXD006135

PXD006135 is an original dataset announced via ProteomeXchange.

Title	Mps1 regulates kinetochore-microtubule attachment stability via the Ska complex to ensure error-free chromosome segregation
Description	Spindle assembly checkpoint (SAC) regulators such as the Mps1 kinase not only delay anaphase onset, but also correct improper chromosome-spindle linkages that would otherwise lead to missegregation and aneuploidy. However, the substrates and mechanisms involved in this pathway of error correction remain poorly understood. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K-fibers) epistatically to Aurora B, the other major error-correcting kinase. Through chemical genetics and quantitative proteomics, we identify both known and novel sites of Mps1- regulated phosphorylation at the outer kinetochore. Modification of these substrates was sensitive to microtubule tension and counterbalanced by the PP2A-B56 phosphatase, a positive regulator of chromosome-spindle interactions. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the hinge region of the W-shaped Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation strongly destabilized K-fibers in vivo and inhibited the Ska complex’s conversion from lattice diffusion to end-coupled microtubule binding in vitro. Together these results provide new insights into how Mps1 modulates the microtubule-binding properties of the kinetochore to promote the selective stabilization of bipolar attachments and error-free chromosome segregation.
HostingRepository	PRIDE
AnnounceDate	2018-10-24
AnnouncementXML	Submission_2018-10-24_15:00:19.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kathrin Grundner-Culemann
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2017-03-21 00:39:51	ID requested
⏵ 1	2018-10-24 15:00:21	announced

Maciejowski J, Drechsler H, Grundner-Culemann K, Ballister ER, Rodriguez-Rodriguez JA, Rodriguez-Bravo V, Jones MJK, Foley E, Lampson MA, Daub H, McAinsh AD, Jallepalli PV, Mps1 Regulates Kinetochore-Microtubule Attachment Stability via the Ska Complex to Ensure Error-Free Chromosome Segregation. Dev Cell, 41(2):143-156.e6(2017) [pubmed]

curator keyword: Biological

submitter keyword: Chemical genetics, proteomics, Spindle assembly checkpoint (SAC), Mps1, PP2A-B56, Ska complex

Prasad V Jallepalli, M.D., Ph.D.
contact affiliation	Memorial Sloan-Kettering Cancer Center, New York, NY UNITED STATES
contact email	jallepap@mskcc.org
lab head
Kathrin Grundner-Culemann
contact affiliation	Evotec (München) GmbH
contact email	kathrin.grundner-culemann@evotec.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/2018/10/PXD006135

PRIDE project URI

• PRIDE
  1. PXD006135
     1. Label: PRIDE project
     2. Name: Mps1 regulates kinetochore-microtubule attachment stability via the Ska complex to ensure error-free chromosome segregation