Cooperative binding of the cationic porphyrin tris-t4 enhances catalytic activity of 20s proteasome unveiling a complex distribution of functional states
Cooperative binding of the cationic porphyrin tris-t4 enhances catalytic activity of 20s proteasome unveiling a complex distribution of functional states(179 views) Santoro AM, D’urso A, Cunsolo A, Milardi D, Purrello R, Sbardella D, Tundo GR, Diana D, Fattorusso R, Di Dato A, Paladino A, Persico M, Coletta M, Fattorusso C
Istituto di Cristallografia-CNR Sede Secondaria di Catania, Via P. Gaifami 9/18, 95126 Catania, Italy.
Dipartimento di Scienze Chimiche, Università Degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
Department of Molecular Medicine, The University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78245, USA.
IRCCS-Fondazione Bietti, 00198 Rome, Italy.
Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli" Via Vivaldi 43, 81100 Caserta, Italy.
Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
Istituto di Chimica del Riconoscimento Molecolare, CNR, Via M. Bianco 9, 20131 Milano, Italy.
Centro Interuniversitario di Ricerca sulla Malaria/Italian Malaria Network, 80131 Napoli, Italy.
References: Not available.
Cooperative binding of the cationic porphyrin tris-t4 enhances catalytic activity of 20s proteasome unveiling a complex distribution of functional states
The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators.
Cooperative binding of the cationic porphyrin tris-t4 enhances catalytic activity of 20s proteasome unveiling a complex distribution of functional states
Cooperative binding of the cationic porphyrin tris-t4 enhances catalytic activity of 20s proteasome unveiling a complex distribution of functional states
Antonini A, Vitale C, Barone P, Cilia R, Righini A, Bonuccelli U, Abbruzzese G, Ramat S, Petrone A, Quatrale R, Marconi R, Ceravolo R, Stefani A, Lopiano L, Zappia M, Capus L, Morgante L, Tamma F, Tinazzi M, Colosimo C, Guerra UP, Valzania F, Fagioli G, Distefano A, Bagnato A, Feggi L, Anna S, Maria Teresa Rosaria De Cr, Nobili F, Mazzuca N, Baldari S, Eleopra R, Bestetti A, Benti R, Varrone A, Volterrani D, Massa R, Stocchi F, Schillaci O, Dore F, Zibetti M, Castellano G, Battista SG, Giorgetti G * The relationship between cerebral vascular disease and parkinsonism: The VADO study(677 views) Parkinsonism Relat D (ISSN: 1353-8020, 1873-5126, 1873-5126electronic), 2012; 18(6): 775-780. Impact Factor:3.274 ViewExport to BibTeXExport to EndNote
Hesse B, Tagil K, Cuocolo A, Anagnostopoulos C, Bardies M, Bax J, Bengel F, Busemann Sokole E, Davies G, Dondi M, Edenbrandt L, Franken P, Kjaer A, Knuuti J, Lassmann M, Ljungberg M, Marcassa C, Marie PY, Mckiddie F, O'connor M, Prvuolovich E, Underwood R * 3. 0 T perfusion MR imaging(1140 views) Rivista Di Neuroradiologia (ISSN: 1120-9976), 2004; 17(6): 807-812. Impact Factor:0.023 ViewExport to BibTeXExport to EndNote