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Molecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2

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cris.lastimport.scopus2024-02-12T20:49:21Z
dc.abstract.enHtrA2 (high-temperature requirement 2) is a human mitochondrial protease that has a role in apoptosis and Parkinson’s disease.The structure of HtrA2 with an intact catalytic triad was determined, revealing a conformational change in the active site loops, involving mainly the regulatory LD loop, which resulted in burial of the catalytic serine relative to the previously reported structure of the proteolytically inactive mutant. Mutations in the loops surrounding the active site that significantly restricted their mobility, reduced proteolytic activity both in vitro and in cells, suggesting that regulation of HtrA2 activity cannot be explained by a simple transition to an activated conformational state with enhanced active site accessibility. Manipulation of solvent viscosity highlighted an unusual bi-phasic behavior of the enzymatic activity, which together with MD calculations supports the importance of motion in the regulation of the activity of HtrA2. HtrA2 is an unusually thermostable enzyme (TM=97.3 °C), a trait often associated with structural rigidity, not dynamic motion. We suggest that this thermostability functions to provide a stable scaffold for the observed loop motions, allowing them a relatively free conformational search within a rather restricted volume.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorAbreu, Rui MV
dc.contributor.authorMoreira, Cátia
dc.contributor.authorPereira, Pedro José Barbosa
dc.contributor.authorMartins, Miguel
dc.contributor.authorMacedo-Ribeiro, Sandra
dc.contributor.authorFernandes, Pedro
dc.contributor.authorRamos, Maria João
dc.contributor.authorMerski, Matthew
dc.date.accessioned2024-01-25T12:53:28Z
dc.date.available2024-01-25T12:53:28Z
dc.date.issued2017
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number10
dc.description.versionFINAL_PUBLISHED
dc.description.volume8
dc.identifier.doi10.1038/CDDIS.2017.487
dc.identifier.issn2041-4889
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/112872
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofCell Death and Disease
dc.relation.pagese3119
dc.rightsCC-BY
dc.sciencecloudnosend
dc.titleMolecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2
dc.typeJournalArticle
dspace.entity.typePublication