Cyclophilin D reduces Ca2+sequestration by complement 1q binding protein

Adegbite, Oluwatobi ORCID: 0000-0002-1731-6883, Adegbite, Yetunde, Pickering, Catrin, Criddle, David N ORCID: 0000-0003-2952-8450 and Lian, Lu-Yun ORCID: 0000-0001-9481-749X (2025) Cyclophilin D reduces Ca2+sequestration by complement 1q binding protein BIOCHEMICAL JOURNAL, 482 (24). pp. 1919-1934. ISSN 0264-6021, 1470-8728

PDF 2025_Adegbite et al_bcj-2025-3361.pdf - Open Access published version Available under License Creative Commons Attribution. Download (5MB) | Preview

Abstract

Complement 1q binding protein (C1qBP) and cyclophilin D (CypD) are mitochondrial matrix proteins; C1qBP has been implicated in many cellular processes, including the regulation of oxidative phosphorylation, and CypD is widely associated with the regulation of mitochondrial permeability transition pore (mPTP) opening. In this study, C1qBP and CypD were shown, in vitro, to form a stable protein–protein complex. CypD–C1qBP interaction was disrupted by cyclosporin A and compromised by mutations of the CypD active site residues R55 and R82. AlphaFold protein modelling revealed that the large negatively charged surface of C1qBP binds to the positive surface of CypD. This electrostatically driven interaction was confirmed by the pH dependence of the protein–protein interaction, with lower affinities observed at higher pH values. C1qBP was shown to undergo conformational changes when bound to Ca²⁺ in vitro, conferring multiple Ca²⁺ interaction sites in a multi-phase process, thereby indicating that C1qBP may act as a Ca²⁺ sequester. In contrast, CypD binding to C1qBP diminished the Ca²⁺-induced conformational changes in C1qBP, lowering its Ca²⁺-binding capacity. Our findings suggest that C1qBP functions as a mitochondrial Ca²⁺ chelator, with its efficiency reduced by CypD, this most likely due to CypD and Ca²⁺ both competing for the same negative surface of C1qBP. The parallels between the features of CypD–C1qBP interaction and the regulation of Ca²⁺-dependent mPTP opening by CypD highlight a possible functional role of CypD which has so far been elusive.

Item Type:	Article
Uncontrolled Keywords:	Humans, Calcium, Cyclosporine, Cyclophilins, Carrier Proteins, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins, Protein Binding, Hydrogen-Ion Concentration, Peptidyl-Prolyl Isomerase F, Peptidyl-Prolyl Isomerase D
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Biochemistry, Cell and Systems Biology
Depositing User:	Symplectic Admin
Date Deposited:	18 Dec 2025 10:28
Last Modified:	16 Jun 2026 17:08
DOI:	10.1042/BCJ20253361
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3196174
Disclaimer:	The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate.