title: Embelin binds to human neuroserpin and impairs its polymerisation.
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.
authors.affiliation: Dipartimento di Bioscienze and CIMAINA, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Saga
authors.affiliation: Dipartimento di Bioscienze and CIMAINA, Università degli Studi di Milano, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sessa
authors.affiliation: Dipartimento di Scienze per gli Alimenti, la Nutrizione e l'Ambiente, Università degli Studi di Milano, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Barbiroli
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Santambrogio
authors.affiliation: Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Russo
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Sala
authors.affiliation: Istituto di Biofisica, National Research Council of Italy, Palermo, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Raccosta
authors.affiliation: Istituto di Biofisica, National Research Council of Italy, Palermo, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Martorana
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina traslazionale, Università degli Studi di Milano, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Caccia
authors.affiliation: Istituto di Biofisica, National Research Council of Italy, Palermo, Italy.
authors.forename: Rosina
authors.initials: R
authors.lastname: Noto
authors.affiliation: Dipartimento di Biologia e Biotecnologie Charles Darwin, and Istituto Pasteur - Fondazione Cenci-Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Moriconi
authors.affiliation: Dipartimento di Biologia e Biotecnologie Charles Darwin, and Istituto Pasteur - Fondazione Cenci-Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Miranda
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università Milano-Bicocca, Milan, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Grandori
authors.affiliation: Istituto di Biofisica, National Research Council of Italy, Palermo, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Manno
authors.affiliation: Dipartimento di Bioscienze and CIMAINA, Università degli Studi di Milano, Milan, Italy.|Istituto di Biofisica, National Research Council of Italy, c/o Dipartimento di Bioscienze, Università degli Studi di Milano, Milan, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
authors.affiliation: Dipartimento di Bioscienze and CIMAINA, Università degli Studi di Milano, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ricagno
mesh_terms: D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods; D009479:Neuropeptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D015843:Serpins / Q000737:chemistry / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors; D000097522:Neuroserpin
chemical_list: D016227:Benzoquinones; D008024:Ligands; D009479:Neuropeptides; D015843:Serpins; D010959:Tissue Plasminogen Activator; D000097522:Neuroserpin; C010945:embelin