1. N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase
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Gabriele Coluccino, Alessandro Negro, Antonio Filippi, Camilla Bean, Valentina Pia Muraca, Clarissa Gissi, Diana Canetti, Maria Chiara Mimmi, Elisa Zamprogno, Francesco Ciscato, Laura Acquasaliente, Vincenzo De Filippis, Marina Comelli, Michela Carraro, Andrea Rasola, Christoph Gerle, Paolo Bernardi, Alessandra Corazza, and Giovanna Lippe
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Biology (General) ,QH301-705.5 - Abstract
Abstract Cyclophilin (CyP) D is a regulator of the mitochondrial F-ATP synthase. Here we report the discovery of a form of CyPD lacking the first 10 (mouse) or 13 (human) N-terminal residues (ΔN-CyPD), a protein region with species-specific features. NMR studies on recombinant human full-length CyPD (FL-CyPD) and ΔN-CyPD form revealed that the N-terminus is highly flexible, in contrast with the rigid globular part. We have studied the interactions of FL and ΔN-CyPD with F-ATP synthase at the OSCP subunit, a site where CyPD binding inhibits catalysis and favors the transition of the enzyme complex to the permeability transition pore. At variance from FL-CyPD, ΔN-CyPD binds OSCP in saline media, indicating that the N-terminus substantially decreases the binding affinity for OSCP. We also provide evidence that calpain 1 is responsible for generation of ΔN-CyPD in cells. Altogether, our work suggests the existence of a novel mechanism of modulation of CyPD through cleavage of its N-terminus that may have significant pathophysiological implications.
- Published
- 2024
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