Dataset Information

Nuclear substrates of the CDKL5 kinase - Phosphoproteomics

ABSTRACT: Identification of nuclear substrates of the CDKL5 kinase by quantitative phosphoproteomics

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Florian Weiland

LAB HEAD: John Rouse

PROVIDER: PXD022916 | Pride | 2020-12-10

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	180405_Uniprot_Homosapiens_canonicalisoforms.fasta	Fasta
	201126_MQ_parameters_Phospho-TMT.xml	Xml
	20190401_HZ_JR_IM_U2OS_CDKL5_TMT10plex_Phos_HighpHRP_01.raw	Raw
	20190401_HZ_JR_IM_U2OS_CDKL5_TMT10plex_Phos_HighpHRP_02.raw	Raw
	20190401_HZ_JR_IM_U2OS_CDKL5_TMT10plex_Phos_HighpHRP_03.raw	Raw

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Project description:Parkinson’s disease (PD) is a prevalent and incurable neurodegenerative disease for which robust biomarkers for early detection and tailored treatment are needed. Protein abundance measurements have so far not proven discriminative as PD biomarkers. Since alterations in protein structure reflect various functionally relevant molecular events, such as allostery, chemical modification, protein misfolding or molecular interaction, we have tested whether global analysis of protein structural changes is informative about PD pathophysiology and status and could form the basis of the new concept of structural biomarkers of disease. We applied limited proteolysis-mass spectrometry (LiP-MS) for the detection of global protein structural changes in cerebrospinal fluid (CSF) of PD patients and age-matched healthy individuals. Using linear modeling to correct for covariates, we identified 76 proteins as structurally altered in the CSF of patients with PD. We identified structural alterations in several proteins implicated in PD, many of which were also structurally altered in PD brain tissue suggesting that this approach provides insight into pathological mechanisms, although validation in independent cohorts is needed. Protein structural information from CSF outperformed protein abundance information in discriminating between healthy and PD subjects. Further, candidate structural biomarkers from our screen provided complementary information to CSF measures of the hallmark PD protein α-synuclein and thus improved the sensitivity and specificity of discriminating the healthy and PD states. Finally, we present the first analysis of inter-individual variability of a structural proteome in healthy humans, identifying biophysical and structural features of variable and invariable protein regions. Structurally variable protein regions show a greater propensity for protein-protein interaction and higher disorder than non-variable peptides. This dataset will be a valuable resource for structural biology and for future structure-based biomarker research. Our data suggest that global analyses of the human structural proteome will lead to the discovery of novel, structural biomarkers of disease and enables hypothesis-generation about the molecular events underlying disease processes.

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Nuclear substrates of the CDKL5 kinase - Phosphoproteomics

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