PXD024683-2

PXD024683 is an original dataset announced via ProteomeXchange.

Title	Rational correction of pathogenic conformational defects in HTRA1
Description	Loss-of-function mutations in the homotrimeric serine protease HTRA1 cause cerebral vasculopathy. Here, we show that disease-causing mutations targeting the protomer-protomer interface impair trimerization. Focusing on a prototypical interface mutation (R274Q), we designed an HTRA1 variant that complemented pathogenic HTRA1 and reconstituted its multimeric assembly and enzymatic activity in vitro. Genetic experiments in Htra1R274Q mice further demonstrated that expression of this protein-based corrector in trans was sufficient to stabilize HTRA1-R274Q and restore the cerebrovascular proteome. As an alternative approach to achieve repair of pathogenic interface mutants, we generated supramolecular chemical ligands that shifted the monomer-trimer equilibrium by stabilizing proteolytically active trimers. Moreover, we identified a peptidic ligand that activated HTRA1 monomers. Collectively, our findings open novel perspectives for tailored protein repair strategies.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:15:47.404.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Stephan Mueller
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-11 07:44:15	ID requested
1	2023-11-24 03:06:47	announced
⏵ 2	2024-10-22 06:15:47	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Mouse, Kidney, Podocytes

Stefan F. Lichtenthaler
contact affiliation	DZNE - German Center for Neurodegenerative Diseases Munich Neuroproteomics Feodor-Lynen Str. 17 D-81377 Munich Germany
contact email	stefan.lichtenthaler@dzne.de
lab head
Stephan Mueller
contact affiliation	DZNE Munich Neuroproteomics
contact email	stephan.mueller@dzne.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024683
     1. Label: PRIDE project
     2. Name: Rational correction of pathogenic conformational defects in HTRA1