Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore

Abstract

Background: Opening of the mitochondrial permeability transition pore is the underlying cause of cellular dysfunction during diverse pathological situations. Although this bioenergetic entity has been studied extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease.

Scope of review: This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents thereby regulating the mitochondrial permeability transition pore.

Major conclusions: While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post-translational modifications of this isomerase and its catalytic activity facilitates pore opening.

General significance: Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.

Keywords: Cyclophilin-D; Mitochondrial permeability transition; Peptidyl-prolyl cis-trans isomerase.

Figure 1. Structural elements of Cyclophilin D

(A) Secondary structure-surface representation denotes a canonical cyclophilin family structure with 8 antiparallel β sheets and 2 well defined α-helices enclosing the sheets. (B) CypD homology rendering comparison between human CypA and CypD using ProtSkin shows high conservation (in orange). Homology is remarkably high in the CsABD, which also encompasses S1 and S2 pockets. Models were retrieved from the Protein Data Bank (PDB ID: 3QYU ) and rendered using Pymol [65].

Figure 2. Structural elements of the CsABD of human Cyclophilin D

(A) Residues involved in the interaction with CsA have hydrophobic (yellow) and polar (green) interactions with CsA. (B) High affinity binding of CsA (orange) completely occludes S1 and S2 pockets and effectively hampers PPIase activity. Models were retrieved from the Protein Data Bank (PDB ID: 3QYU ) and rendered using Pymol [65].

Figure 3. Cartoon sequences showing sequential rotations of human CypD

All serines (green) and threonines (yellow) are represented in sphere projection. Residues C203 (magenta) and K175 (white) are located in the backface of CypD, whereas conserved S123 (purple) is located in the CsABD. Previously proposed residues of CypD involving PTMs are pointed with an arrow. Models were retrieved from the Protein Data Bank (PDB ID: 3QYU ) and rendered using Pymol [65].

Figure 4. Current proposed protein complexes influencing the MPT pore

In this figure, ATP synthase (blue) is represented in the dimeric form and interacts with CypD (yellow) at the level of OSCP. CypD can also interact with ANT (red) or PiC (orange). Models were retrieved from the Protein Data Bank (except for the PiC, which was modeled previously [20]) and rendered using Pymol [65].