Embelin binds to human neuroserpin and impairs its polymerisation.

Giorgia Saga,Alberto Barbiroli,Sonia Caccia,Rita Grandori,Rosina Noto,Martino Bolognesi,Vincenzo Martorana,Mauro Manno,Michela Sala,Stefano Ricagno,Fabio Sessa,Claudia Moriconi,Rosaria Russo,Carlo Santambrogio,Elena Miranda,Samuele Raccosta

doi:10.1038/srep18769

Giorgia Saga, Alberto Barbiroli + Show 14 more

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https://doi.org/10.1038/srep18769

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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.

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Neuroserpin (SERPINI1) (NS) is a member of the serpin superfamily, whose members are mainly serine-protease inhibitors[1]
Cleaved NS (Cle), if present as in the experiment shown in figure S2B, is eluted only in the monomeric fractions, while the latent conformation (Lat) conformer typically formed during incubation of Nat at high temperatures[23] is virtually absent (Fig. S2B,C)
Analysis of the incubation and elution data reported suggests that the oligomerisation may occur according to the following steps: first the species eluted at 13.7 ml peak is formed, followed by one eluted at 12.5 ml; most NS accumulates in the broad peak centred around 9.5 ml, while the 13.7 ml peak disappears (Fig. S2C,D)

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Introduction

Neuroserpin (SERPINI1) (NS) is a member of the serpin superfamily, whose members are mainly serine-protease inhibitors[1]. Cleaved NS (Cle), if present as in the experiment shown, is eluted only in the monomeric fractions, while the Lat conformer typically formed during incubation of Nat at high temperatures[23] is virtually absent (Fig. S2B,C).

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