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, i.e. 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.

Embelin binds to human neuroserpin and impairs its polymerisation / G. Saga, F. Sessa, A. Barbiroli, C. Santambrogio, R. Russo, M. Sala, S. Raccosta, V. Martorana, S. Caccia, R. Noto, C. Moriconi, E. Miranda, R. Grandori, M. Manno, M. Bolognesi, S. Ricagno. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6(2016 Jan 06), pp. 18769.1-18769.12.

Embelin binds to human neuroserpin and impairs its polymerisation

A. Barbiroli;R. Russo;S. Caccia;M. Bolognesi
Penultimo
;
S. Ricagno
2016

Abstract

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, i.e. 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.
plasminogen-activator inhibitor-1; inclusion-bodies; forms polymers; familial encephalopathy; proteinase-inhibitor; molecular-basis; ementia fenib; serpin; alpha(1)-antitrypsin; latent
Settore BIO/10 - Biochimica
Settore BIO/11 - Biologia Molecolare
6-gen-2016
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/356189
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