Department of Medicine, University of Udine, 33100, Udine, Italy.
Department of Biomedical Sciences, University of Padova, 35131, Padova, Italy.
Commun Biol. 2024 Nov 11;7(1):1486. doi: 10.1038/s42003-024-07172-8.
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.
亲环素 D（CyP）是线粒体 F-ATP 合酶的调节因子。在这里，我们报告了一种缺乏第一个 10 个（鼠）或 13 个（人）N 端残基（ΔN-CyPD）的 CyPD 形式的发现，这是一个具有种属特异性特征的蛋白质区域。对重组人全长 CyPD（FL-CyPD）和 ΔN-CyPD 形式的 NMR 研究表明，N 端非常灵活，与刚性球状部分形成对比。我们研究了 FL 和 ΔN-CyPD 与 OSCP 亚基的 F-ATP 合酶的相互作用，CyPD 结合在此位点抑制催化作用，并有利于酶复合物向通透性转变孔的转变。与 FL-CyPD 不同，ΔN-CyPD 在盐溶液介质中与 OSCP 结合，表明 N 端大大降低了与 OSCP 的结合亲和力。我们还提供了证据表明钙蛋白酶 1 负责细胞中 ΔN-CyPD 的产生。总的来说，我们的工作表明通过切割其 N 端存在一种调节 CyPD 的新机制，这可能具有重要的病理生理学意义。
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