Embelin binds to human neuroserpin and impairs its polymerisation

Medientyp: E-Artikel
Titel: Embelin binds to human neuroserpin and impairs its polymerisation
Beteiligte: Saga, Giorgia; Sessa, Fabio; Barbiroli, Alberto; Santambrogio, Carlo; Russo, Rosaria; Sala, Michela; Raccosta, Samuele; Martorana, Vincenzo; Caccia, Sonia; Noto, Rosina; Moriconi, Claudia; Miranda, Elena; Grandori, Rita; Manno, Mauro; Bolognesi, Martino; Ricagno, Stefano
Erschienen: Springer Science and Business Media LLC, 2016
Erschienen in: Scientific Reports
Sprache: Englisch
DOI: 10.1038/srep18769
ISSN: 2045-2322
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>Neuroserpin (NS) is a serpin inhibitor of tissue plasminogen activator (tPA) in the brain. The polymerisation of NS pathologic mutants is responsible for a genetic dementia known as familial encephalopathy with neuroserpin inclusion bodies (FENIB). So far, a pharmacological treatment of FENIB, <jats:italic>i.e.</jats:italic> an inhibitor of NS polymerisation, remains an unmet challenge. Here, we present a biophysical characterisation of the effects caused by embelin (EMB a small natural compound) on NS conformers and NS polymerisation. EMB destabilises all known NS conformers, specifically binding to NS molecules with a 1:1 NS:EMB molar ratio without unfolding the NS fold. In particular, NS polymers disaggregate in the presence of EMB and their formation is prevented. The NS/EMB complex does not inhibit tPA proteolytic activity. Both effects are pharmacologically relevant: firstly by inhibiting the NS polymerisation associated to FENIB and secondly by potentially antagonizing metastatic processes facilitated by NS activity in the brain.</jats:p>
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