N-terminal cleavage of cyclophilin D boosts its ability to bind F-ATP synthase.

Autor: Coluccino, Gabriele, Negro, Alessandro, Filippi, Antonio, Bean, Camilla, Muraca, Valentina Pia, Gissi, Clarissa, Canetti, Diana, Mimmi, Maria Chiara, Zamprogno, Elisa, Ciscato, Francesco, Acquasaliente, Laura, De Filippis, Vincenzo, Comelli, Marina, Carraro, Michela, Rasola, Andrea, Gerle, Christoph, Bernardi, Paolo, Corazza, Alessandra, Lippe, Giovanna
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Zdroj: Communications Biology; 11/11/2024, Vol. 7 Issue 1, p1-15, 15p
Abstrakt: 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. Mitochondrial Cyclophilin D can be cleaved at the N-terminus, resulting in a truncated form with enhanced binding to the OSCP subunit of F-ATP Synthase. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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