N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase
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.
Authors
- Paolo Bernardi (ORCID: https://orcid.org/0000-0001-9187-3736)
- Alessandra Corazza (ORCID: https://orcid.org/0000-0003-2272-1928)
- Michela Carraro (ORCID: https://orcid.org/0000-0002-4573-9306)
- Alessandro Negro (ORCID: https://orcid.org/0000-0003-3142-7632)
- Camilla Bean (ORCID: https://orcid.org/0000-0001-6491-7211)
- Christoph Gerle (ORCID: https://orcid.org/0000-0002-7265-2804)
- Clarissa Gissi (ORCID: https://orcid.org/0000-0002-6411-1485)
- Antonio Filippi (ORCID: https://orcid.org/0000-0003-4308-8746)
- Diana Canetti (ORCID: https://orcid.org/0000-0001-5292-8124)
- Giovanna Lippe (ORCID: https://orcid.org/0000-0003-0042-5052)
- Maria Chiara Mimmi (ORCID: https://orcid.org/0000-0002-5165-9230)
- Gabriele Coluccino
- Andrea Rasola (ORCID: https://orcid.org/0000-0003-4522-3008)
- Francesco Ciscato (ORCID: https://orcid.org/0000-0003-2298-1439)
- Laura Acquasaliente (ORCID: https://orcid.org/0000-0001-6495-0871)
- Valentina Pia Muraca
- Vincenzo De Filippis (ORCID: https://orcid.org/0000-0001-9775-8894)
- Elisa Zamprogno
- Marina Comelli
Institutions
- University of Udine (IT)
- University of Padua (IT)
- SPring-8 (JP)
- Neuroscience Institute (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- National Research Council (IT)
- University College London (GB)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1038/s42003-024-07172-8
- Citations
- 7
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università degli Studi di Padova
- Università degli Studi di Pavia
- Università degli Studi di Udine