PXD028923

PXD028923 is an original dataset announced via ProteomeXchange.

Title	The conformational state of PLCγ cSH2-linker contributes to Ibrutinib resistance
Description	Mutations in PLCγ, a substrate of the tyrosine kinase BTK, are often found in patients who develop resistance to the BTK inhibitor Ibrutinib. However, the mechanisms by which these PLCγ mutations cause Ibrutinib resistance are unclear. Under normal signaling conditions, BTK mediated phosphorylation of Y783 within the PLCγ cSH2-linker promotes the intramolecular association of this site with the adjacent cSH2 domain resulting in active PLCγ. Thus, the cSH2-linker region in the center of the regulatory gamma specific array (γSA) of PLCγ is a key feature controlling PLCγ activity. Even in the unphosphorylated state this linker exists in a conformational equilibrium between free and bound to the cSH2 domain. The position of this equilibrium is optimized within the properly regulated PLCγ enzyme but may be altered in the context of mutations. We therefore assessed the conformational status of four resistance associated mutations within the PLCγ γSA and find that they each alter the conformational equilibrium of the γSA leading to a shift toward active PLCγ. Interestingly, two distinct modes of mutation induced activation are revealed by this panel of Ibrutinib resistance mutations. These findings, along with the recently determined structure of fully autoinhibited PLCγ, provide new insight into the nature of the conformational change that occurs within the γSA regulatory region to affect PLCγ activation. Improving our mechanistic understanding of how B cell signaling escapes Ibrutinib treatment via mutations in PLCγ will aid in the development of strategies to counter drug resistance.
HostingRepository	PRIDE
AnnounceDate	2022-01-25
AnnouncementXML	Submission_2022-01-25_07:08:39.263.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John R. Engen
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-04 10:01:29	ID requested
⏵ 1	2022-01-25 07:08:40	announced

Joseph RE, Lowe J, Fulton DB, Engen JR, Wales TE, Andreotti AH, Contributes to Ibrutinib Resistance. J Mol Biol, 434(5):167422(2022) [pubmed]

submitter keyword: PLCγ

Phospholipase C gamma

Ibrutinib resistance

allostery

HDX-MS

hydrogen/deuterium exchange mass spectrometry

NMR

SH2 domain.

John R. Engen
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University
contact email	j.engen@northeastern.edu
lab head
John R. Engen
contact affiliation	Northeastern University
contact email	j.engen@northeastern.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/2022/01/PXD028923

PRIDE project URI

• PRIDE
  1. PXD028923
     1. Label: PRIDE project
     2. Name: The conformational state of PLCγ cSH2-linker contributes to Ibrutinib resistance