PXD044990-1

PXD044990 is an original dataset announced via ProteomeXchange.

Title	Redox Regulation of Brain Selective Kinases BRSK1/2: Implications for Dynamic Control of the Eukaryotic AMPK family through Cys-based mechanisms
Description	In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications (PTMs). While regulation by activation segment phosphorylation in Ser/Thr kinases is well understood, relatively little is known about how oxidation of cysteine (Cys) amino acids modulates catalysis. In this study, we investigate redox regulation of the AMPK-related Brain-selective kinases (BRSK) 1 and 2, and detail how broad catalytic activity is directly regulated through reversible oxidation and reduction of evolutionarily conserved Cys residues within the catalytic domain. We show that redox-dependent control of BRSKs is a dynamic and multilayered process involving oxidative modifications of several Cys residues, including the formation of intra-molecular disulfide bonds involving a pair of Cys residues near the catalytic HRD motif, a highly conserved T-Loop Cys and a BRSK-specific Cys within an unusual CPE motif at the end of the activation segment. Consistently, mutation of the CPE-Cys increases catalytic activity in vitro and drives phosphorylation of the BRSK substrate Tau in cells. Molecular modeling and molecular dynamics simulations indicate that oxidation of the CPE-Cys destabilizes a conserved salt bridge network critical for allosteric activation. The occurrence of spatially proximal Cys amino acids in diverse Ser/Thr protein kinase families suggests that disulfide mediated control of catalytic activity may be a prevalent mechanism for regulation within the broader AMPK family.
HostingRepository	PRIDE
AnnounceDate	2025-04-01
AnnouncementXML	Submission_2025-04-01_02:13:18.981.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD044990
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	leonard daly
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; disulfide crosslinked residues; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-31 01:49:14	ID requested
⏵ 1	2025-04-01 02:13:19	announced

10.6019/PXD044990;

submitter keyword: BRSK1, Redox, Disulfide, BRSK2, Cysteine

Prof Claire Eyers
contact affiliation	Centre for Proteome Research, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
contact email	ceyers@liverpool.ac.uk
lab head
leonard daly
contact affiliation	University of Liverpool
contact email	leonard.daly@liverpool.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044990
     1. Label: PRIDE project
     2. Name: Redox Regulation of Brain Selective Kinases BRSK1/2: Implications for Dynamic Control of the Eukaryotic AMPK family through Cys-based mechanisms