Dataset Information

MS analysis of an FGE-PDI complex

ABSTRACT: Multiple Sulfatase Deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterised by reduced activities of all cellular sulfatases in patients. Sulfatases require a unique post-translational modification of an active site cysteine to formylglycine that is catalysed by the Formylglycine Generating Enzyme (FGE). FGE mutations leading to MSD affect the intracellular protein stability that determines residual enzyme activity and defines disease severity in MSD patients. Here, we show that Protein Disulfide Isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of sulfatases in MSD fibroblasts. Analysing a covalent complex consisting of PDI and a FGE variant by LC-MALDI mass spectrometry allowed to determine the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may be relevant also for other ER-associated protein folding pathologies.

INSTRUMENT(S): ultraflex

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Bernhard Schmidt

LAB HEAD: Bernhard Schmidt

PROVIDER: PXD009758 | Pride | 2018-07-04

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	1764_search_result.dat	Other
	Archive.zip	Other

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Publications

Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase.

Schlotawa Lars L Wachs Michaela M Bernhard Olaf O Mayer Franz J FJ Dierks Thomas T Schmidt Bernhard B Radhakrishnan Karthikeyan K

Cell reports 20180701 1

Multiple sulfatase deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (P ...[more]

PMID: 29972788

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