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Protein family review

The cyclophilins

Ping Wang1* and Joseph Heitman2

Author Affiliations

1 The Research Institute for Children, Children's Hospital, and Departments of Pediatrics, and Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA

2 Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA

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Genome Biology 2005, 6:226  doi:10.1186/gb-2005-6-7-226

The electronic version of this article is the complete one and can be found online at: http://genomebiology.com/2005/6/7/226


Published:27 June 2005

© 2005 BioMed Central Ltd

Abstract

Summary

Cyclophilins (Enzyme Commission (EC) number 5.1.2.8) belong to a group of proteins that have peptidyl-prolyl cis-trans isomerase activity; such proteins are collectively known as immunophilins and also include the FK-506-binding proteins and the parvulins. Cyclophilins are found in all cells of all organisms studied, in both prokaryotes and eukaryotes; humans have a total of 16 cyclophilin proteins, Arabidopsis up to 29 and Saccharomyces 8. The first member of the cyclophilins to be identified in mammals, cyclophilin A, is the major cellular target for, and thus mediates the actions of, the immunosuppressive drug cyclosporin A. Cyclophilin A forms a ternary complex with cyclosporin A and the calcium-calmodulin-activated serine/threonine-specific protein phosphatase calcineurin; formation of this complex prevents calcineurin from regulating cytokine gene transcription. Recent studies have implicated a diverse array of additional cellular functions for cyclophilins, including roles as chaperones and in cell signaling.

Gene organization and evolutionary history

The terms 'cyclophilin' and 'peptidyl-prolyl isomerase' (PPIase) are almost synonymous today, but the identification of the first protein that showed PPIase activity over 20 years ago [1] was independent of the purification of cyclophilin A (CypA) from bovine thymocytes as an intracellular protein with a high affinity for the immunosuppressive drug cyclosporin A (CsA) [2]. It was not until five years later that the 18 kDa protein with PPIase activity and CypA were found to be one and the same [3,4]. Along with the discoveries of other PPIase proteins (immunophilins), such as the parvulins and the FK-506-binding proteins (FKBPs, which bind the immunosuppressant drug FK-506), additional cyclophilins have subsequently been identified and the cyclophilins were found to constitute a protein family. All cyclophilins share a common domain of approximately 109 amino acids, the cyclophilin-like domain (CLD), surrounded by domains unique to each member of the family that are associated with subcellular compartmentalization and functional specialization [5,6].

Cyclophilins have been found in mammals, plants, insects, fungi, and bacteria; they are structurally conserved throughout evolution and all have PPIase activity. There are 7 major cyclophilins in humans - hCypA (also called hCyp-18a, 18 denotes molecular mass of 18 kDa), hCypB (also called hCyp-22/p, 22 kDa), hCypC, hCypD, hCypE, hCyp40 (40 kDa), and hCypNK (first identified from human natural killer cells) - and a total of 16 unique proteins [7,8]. Drosophila has at least 9 cyclophilins [7] and the plant Arabidopsis thaliana has 29 putative cyclophilins [9], whereas 8 cyclophilins, Cpr1-Cpr8, have been found in Saccharomyces cerevisiae (reviewed in [6]). Little is known about the genomic structure of human cyclophilin genes; they are generally not linked to each other in the genome.

What is peptidyl-prolyl isomerization and why does it require a catalyst? The peptide bond has a partial double-bond character, and like all double bonds with similar combinations of side chains, it can exist in two distinct isomeric forms: cis and trans. The lower energy-state trans peptide bonds, whose side chains are 180 degrees opposite each other, are sterically favored, and the ribosome is thought to synthesize peptide bonds in this form. In many proteins containing proline, however, the bonds preceding each proline (peptidyl-prolyl bonds) also occur in the cis form, with the side chains adjacent to each other; both de novo protein folding and the refolding processes following cellular membrane traffic necessitate isomerization to the cis form. Spontaneous isomerization of peptidyl-prolyl bonds requires free energy and is a slow process, particularly at lower temperatures, and it constitutes a rate-limiting step in folding. Cyclophilins stabilize the cis-trans transition state and accelerate isomerization, a process that is considered important not only in protein folding but also during the assembly of multidomain proteins (Figure 1) [10]. Regardless of their origin, the structural conservation of cyclophilins throughout evolution and the PPIase activity of all members underlines the importance of this enzymatic reaction.

thumbnailFigure 1. A schematic illustration of the trans and cis isomers of the peptide bond between proline (on the left of each structure shown) and another amino acid (P1, on the right). The interconversion between the two forms is catalyzed by cyclophilins and other peptidyl-prolyl isomerases (PPIases) [7]. The carbon atoms of the proline are indicated by Greek letters; P2 indicates a third amino acid on the other side of the proline. The peptide bond has some double-bond character and is planar.

Cyclophilins also have varying degrees of affinity for the immunosuppressive drug CsA, a cyclic 11-amino-acid peptide produced by the fungus Tolypocladium inflatum. CypA, in particular, is the major intracellular receptor for CsA [2]. In mammals, the CsA-CypA complex binds to and inhibits calcineurin, a calcium-calmodulin-activated serine/threonine-specific protein phosphatase. The inhibition of calcineurin blocks the translocation of nuclear factor of activated T cells (NF-AT) from the cytosol to the nucleus, thus preventing the transcription of genes encoding cytokines such as interleukin-2 [11,12]. In the yeast S. cerevisiae, inhibition of the calcineurin homolog by the complex between CsA and the cyclophilin A homolog Cpr1 prevents recovery from pheromone-induced growth arrest [13]. In the human-pathogenic fungus Cryptococcus neoformans, inhibition of the calcineurin homolog Cna1 by a complex of CsA with either of the cyclophilin A homologs Cpal or Cpa2 prevents growth at elevated temperatures [14,15].

Characteristic structural features

The 18-kDa archetypal cyclophilin CypA is cytosolic and found in all tissues in mammals, whereas other cyclophilins, whether they have a CLD alone or in combination with other domains, are found in the endoplasmic reticulum (ER), the mitochondria, or the nucleus. The crystal structures of several cyclophilins have been determined (reviewed in [16]). Human CypA has an eight-stranded antiparallel β-barrel structure, with two α helices enclosing the barrel from either side (Figure 2). Seven aromatic and other hydrophobic residues form a compact hydrophobic core within the barrel, usually in the area where CsA binds. A loop from Lys118 to His126 and four β strands (β3-β6) make up the binding site for CsA [17,18]. The overall structure of hCypB resembles that of hCypA, the main difference being in the two loop regions (residues 19-24 and 152-164) and at the amino and carboxyl termini [19]. Murine CypC also has a structure similar to that of hCypA, differing mainly in the conformation of three surface loop regions [20]. The large cyclophilin Cyp40 consists of a CLD with a structure similar to that of hCypA linked to tetratricopeptide repeats (TPRs), which are also found in proteins involved in stress responses. Structural analysis reveals that the TPR domain of Cyp40 consists of seven helices of variable lengths incorporating three TPR motifs. Cyp40 crystals come in two shapes: in the monoclinic form, the carboxy-terminal residues protrude beyond the body of the TPR domain to form a charged helix, whereas in the tetragonal form two of the TPR helices are straightened to form one extended helix [21].

thumbnailFigure 2. The structure of the ternary complex between the drug cyclosporin A (CsA), human cyclophilin A (CypA) and human calcineurin [37]. The CsA-CypA binary complex lies at the base of the helical arm of the catalytic subunit of calcineurin (CnA) that binds the regulatory subunit calcineurin (CnB); it nestles in a hydrophobic groove in intimate contact with both subunits, at a region unique to calcineurin and not found in other phosphatases, and this intimate contact gives the interaction high specificity. Reproduced with permission from [37].

Localization and function

Cyclophilins can be found in most cellular compartments of most tissues and encode unique functions. In mammals, CypA and Cyp40 are cytosolic whereas CypB and CypC have amino-terminal signal sequences that target them to the ER protein secretory pathway (reviewed in [7,16]). CypD has a signal sequence that directs it to the mitochondria [22,23]; CypE has an amino-terminal RNA-binding domain and is localized in the nucleus [24] and Cyp40 has TPRs and is located in the cytosol [25]. Human CypNK is the largest cyclophilin, with a large, hydrophilic and positively charged carboxyl terminus, and is located in the cytosol [26,27].

The yeast cyclophilin Cpr1 is a homolog of hCypA that shares 65% identity in amino-acid sequence and is present in the cytoplasm and also enriched in nuclei [28,29]. Cpr2, Cpr3, and Cpr5 have amino-terminal signal peptides directing them to the ER (Cpr2 and Cpr5 [30,31]) or the mitochondria (Cpr3 [32,33]; Figure 3). Cpr4 and Cpr8 contain a single CLD domain plus a long amino-terminal signal peptide and are located in vacuoles [34]. Lastly, Cpr6 and Cpr7 are homologs of the human Cyp40 protein and have long carboxy-terminal TPR repeats; they associate functionally with homologs of heat-shock proteins and other protein chaperones [35]. The primary structures and localizations of the yeast cyclophilins, as well as their mammalian orthologs, are summarized in Figure 3.

thumbnailFigure 3. Primary structures, localizations and mammalian orthologs of S. cerevisiae cyclophilins [6]. Abbreviations: CLD, cyclophilin-like domain; ER, ER retention signal; M, mitochondrial localization signal; SP, signal peptide; TM, transmembrane domain; TPR, tetratricopeptide repeat.

Functions of mammalian cyclophilins

The immunosuppressive action of CsA is exerted via a ternary complex between CsA, CypA and calcineurin. The crystal structure of the complex has recently been determined to a resolution of 2.8 Å (Figure 2) [36,37]. Binding of the CsA-CypA complex to calcineurin increases the complex's stability, and the complexed proteins remain resistant to proteolytic cleavage [38]. Upon binding of CsA to CypA, the charges and hydrophobic surfaces of the drug-protein complex become more congruent with the binding site on calcineurin. The CsA-CypA complex binds at the interface between the catalytic and regulatory subunits of calcineurin (Figure 2). Most importantly, CsA-CypA binding to calcineurin inhibits the phosphatase activity and biological function of calcineurin [11,13,39,40].

Several protein-folding processes depend on the catalytic and/or chaperone-like activities of cyclophilins. For example, CypA promotes both the formation and the infectivity of virions of the human immunodeficiency virus (HIV)-1 [41-47]. CypA is incorporated into HIV-1 virions, where it interacts with HIV-1 Gag, the polyprotein precursor of virion structural proteins. A small region of the HIV-1 capsid protein containing four conserved prolines has been shown to be important for incorporation of CypA into virions [48,49].

A retina-specific cyclophilin of the fruit fly Drosophila melanogaster, NinaA (an ortholog of mammal CypC), is crucial for the folding of rhodopsin isoforms [50,51]. A mutation in the gene encoding NinaA results in improper folding of rhodopsin and subsequent abnormal expression of the protein [50]. CypA is also important in the folding of neu-ronal receptors. Using CsA to probe the expression of homo-oligomeric receptors containing nicotinic acetylcholine receptor subunit α7, Helekar and colleagues [52] concluded that CypA might have a critical role in the maturation of homo-oligomeric receptors by acting directly or indirectly as a prolyl isomerase or as a molecular chaperone.

Cyclophilins can also act as modulators of protein function. The mammalian cyclophilin Cyp40 is part of the steroid-receptor complex and can form a dimeric complex with the heat-shock protein Hsp90, a process not affected by CsA [53,54]. In yeast, the Cyp40 homologs Cpr6 and Cpr7 also associate with Hsp90 homologs and have analogous functions [6]. A mammalian Cyp40 has been shown to regulate the activity of the transcription factor c-Myb [55], whereas CypA has been associated with YY1, a zinc-finger suppressor of gene transcription [56], and Zpr1, an essential zinc-finger protein [57]. In addition, the ER-specific cyclophilin CypB can form a complex with the peptide hormone prolactin to induce transcription of a range of genes [58].

Functions of yeast cyclophilins

Contrary to the expectation that the highly conserved cyclophilins might be essential for protein folding, none of the eight individual cyclophilins was found to be essential in S. cerevisiae [59]. In fact, we showed that an octuplet mutant lacking all eight cyclophilins was viable and that there was little or no evidence for functional redundancy [59]. Recent studies also reveal that Cpr1 has a role in modulating the activity of two different histone-deacetylase complexes (Sin3-Rpd3 and Set3C) and is important in enabling the transcriptional events necessary during the switch from mitotic to meiotic cell division in budding yeast [29,60,61]. This is in accord with our recent finding that Cpr1 is enriched in the nucleus in yeast cells, and it reveals a clear selective pressure for maintaining this highly conserved enzyme [29].

The pathogenic yeast C. neoformans has two similar CypA-related proteins, Cpa1 and Cpa2. In contrast to the viable octuplet cyclophilin mutant strain of S. cerevisiae, Cpa1 is required for growth of C. neoformans at elevated temperatures and for full expression of fungal virulence, whereas Cpa2 is dispensable for these functions in the presence of Cpa1. Deletion of both the CPA1 and CPA2 genes leads to a conditional synthetic phenotype, resulting in a defect in growth and virulence [62]. In our current models, this role of Cpa1 and Cpa2 is hypothesized to be independent of calcineurin function, suggesting a novel role for cyclophilin A homologs in the growth and virulence of this pathogen [62].

Frontiers

Recent studies have suggested a new role for cyclophilins in cell signaling. For example, mammalian CypA has been found to regulate the T-cell-specific interleukin-2 tyrosine kinase Itk, which contains conserved Src homology 2 (SH2), Src homology 3 (SH3), and kinase domains [63-65]. Itk is a non-receptor protein-tyrosine kinase that has a role in the maturation of thymocytes and is required for intracellular signaling events leading to T-cell activation. Binding of CypA to the SH2 domain of Itk results in conformational change within the SH2 domain that alters ligand specificity [63]. Mutation of a proline residue in the SH2 domain disrupts the interaction between Itk and CypA and specifically increases the production of type 2 (Th2) cytokines (cytokines produced by Th2 helper cells) [65,66].

In another example of a cyclophilin involved in cell signaling, human CypB has been found to govern the activation of interferon-regulatory factor-3 (IRF-3). IRF-3 is a member of the group of interferon regulatory factors that induce interferon-β once translocated into the nucleus. CypB interacts with IRF-3 in the yeast two-hybrid assay. An RNA-interference study of CypB indicates that the suppression of virus-induced IRF-3 phosphorylation and other related events can result in the inhibition of interferon-1β [67].

Finally, the mitochondrially targeted cyclophilin CypD has been found to play an important role in the mitochondrial permeability transition, in which mitochondrial pores open, leading to cell death [68-72]. By generating CypD-deficient mice, several research groups have discovered that CypD and the mitochondrial permeability transition are required to mediate the cell death induced by calcium and oxidative damage, but not to mediate conventional apoptosis involving Bcl-2 family proteins [70-72]. Further exploration of the role of CypD in mitochondrial function and its potential as a novel drug target has been also discussed recently [8].

Acknowledgements

We thank Hengming Ke for providing Figure 2 and J.A. King for careful reading of the manuscript. Research in the Wang and Heitman laboratories is supported by NIH grants A1054958 (P.W.), A103911I5, A1042159, A1050113, and A1050438 (J.H.). J.H. is a Burroughs-Wellcome Scholar in Molecular Pathogenic Mycology and an investigator of the Howard Hughes Medical Institute.

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    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  46. Braaten D, Luban J: Cyclophilin A regulates HIV-1 infectivity, as demonstrated by gene targeting in human T cells.

    EMBO J 2001, 20:1300-1309.

    See [41].

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  47. Sokolskaja E, Sayah DM, Luban J: Target cell cyclophilin A modulates human immunodeficiency virus type 1 infectivity.

    J Virol 2004, 78:12800-12808.

    See [41].

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  48. Franke EK, Yuan HE, Luban J: Specific incorporation of cyclophilin A into HIV-1 virions.

    Nature 1994, 372:359-362.

    See [41].

    PubMed Abstract | Publisher Full Text OpenURL

  49. Thali M, Bukovsky A, Kondo E, Rosenwirth B, Walsh CT, Sodroski J, Gottlinger HG: Functional association of cyclophilin A with HIV-1 virions.

    Nature 1994, 372:363-365.

    See [41].

    PubMed Abstract | Publisher Full Text OpenURL

  50. Stamnes MA, Shieh BH, Chuman L, Harris GL, Zuker CS: The cyclophilin homolog ninaA is a tissue-specific integral membrane protein required for the proper synthesis of a subset of Drosophila rhodopsins.

    Cell 1991, 65:219-227.

    This paper and [51] report the role of NinaA in the synthesis of Drosophila rhodopsins.

    PubMed Abstract | Publisher Full Text OpenURL

  51. Colley NJ, Baker EK, Stamnes MA, Zuker CS: The cyclophilin homolog ninaA is required in the secretory pathway.

    Cell 1991, 67:255-263.

    See [50].

    PubMed Abstract | Publisher Full Text OpenURL

  52. Helekar SA, Char D, Neff S, Patrick J: Prolyl isomerase requirement for the expression of functional homo-oligomeric ligand-gated ion channels.

    Neuron 1994, 12:179-189.

    This report suggests that cyclophilins may play a role in the maturation of homo-oligomeric receptors.

    PubMed Abstract | Publisher Full Text OpenURL

  53. Ratajczak T, Carrello A, Mark PJ, Warner BJ, Simpson RJ, Moritz RL, House AK: The cyclophilin component of the unactivated estrogen receptor contains a tetratricopeptide repeat domain and shares identity with p59 (FKBP59).

    J Biol Chem 1993, 268:13187-13192.

    This paper and [54] show that Cyp40 is a part of the steroid-receptor complex.

    PubMed Abstract | Publisher Full Text OpenURL

  54. Chang HC, Lindquist S: Conservation of Hsp90 macromolecular complexes in Saccharomyces cerevisiae.

    J Biol Chem 1994, 269:24983-24988.

    See [53].

    PubMed Abstract | Publisher Full Text OpenURL

  55. Leverson JD, Ness SA: Point mutations in v-Myb disrupt a cyclophilin-catalyzed negative regulatory mechanism.

    Mol Cell 1998, 1:203-211.

    This study shows that Cyp40 inhibits the c-Myb DNA binding activity.

    PubMed Abstract | Publisher Full Text OpenURL

  56. Yang WM, Inouye CJ, Seto E: Cyclophilin A and FKBP12 interact with YY1 and alter its transcriptional activity.

    J Biol Chem 1995, 270:15187-15193.

    Immunophilins modulate the zinc-finger transcription factor YY1.

    PubMed Abstract | Publisher Full Text OpenURL

  57. Ansari H, Greco G, Luban J: Cyclophilin A peptidyl-prolyl isomerase activity promotes ZPR1 nuclear export.

    Mol Cell Biol 2002, 22:6993-7003.

    This report shows that the yeast Cpr1 modulates the function of the zinc-finger transcription factor Zpr1 by promoting its nuclear export.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  58. Rycyzyn MA, Clevenger CV: The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer.

    Proc Natl Acad Sci USA 2002, 99:6790-6795.

    This study reports the interaction between CypB and the somatolactogenic hormone prolactin.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  59. Dolinski K, Muir S, Cardenas M, Heitman J: All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae.

    Proc Natl Acad Sci USA 1997, 94:13093-13098.

    A report of a yeast dodecuplet mutant strain in which all 12 genes encoding 8 cyclophilins and 4 FKBPs were deleted.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  60. Arevalo-Rodriguez M, Cardenas ME, Wu X, Hanes SD, Heitman J: Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase.

    EMBO J 2000, 19:3739-3749.

    This study shows that the yeast Cpr1 and parvilin Ess1 function in parallel, both targeting the Sin3-Rpd3 histone-deacetylase complex.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  61. Pijnappel WW, Schaft D, Roguev A, Shevchenko A, Tekotte H, Wilm M, Rigaut G, Seraphin B, Aasland R, Stewart AF: The S. cerevisiae SET3 complex includes two histone deacetylases, Hos2 and Hst1, and is a meiotic-specific repressor of the sporulation gene program.

    Genes Dev 2001, 15:2991-3004.

    This study reports that the yeast Cpr1 is a part of the Set3 complex that maintains histone-deacetylase activities.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  62. Wang P, Cardenas ME, Cox GM, Perfect JR, Heitman J: Two cyclophilin A homologs with shared and distinct functions important for growth and virulence of Cryptococcus neoformans.

    EMBO Rep 2001, 2:511-518.

    A description of the function of two cyclophilin A homologs in the pathogenic fungus C. neoformans.

    PubMed Abstract | Publisher Full Text OpenURL

  63. Brazin KN, Mallis RJ, Fulton DB, Andreotti AH: Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A.

    Proc Natl Acad Sci USA 2002, 99:1899-1904.

    This paper and [65] give evidence that CypA inhibits the catalytic activity of the tyrosine kinase Itk.

    PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  64. Min L, Fulton DB, Andreotti AH: A case study of proline isomerization in cell signaling.

    Front Biosci 2005, 10:385-397.

    An overview of the role of CypA in the regulation of Itk.

    PubMed Abstract | Publisher Full Text OpenURL

  65. Colgan J, Asmal M, Neagu M, Yu B, Schneidkraut J, Lee Y, Sokolskaja E, Andreotti A, Luban J: Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk.

    Immunity 2004, 21:189-201.

    See [63].

    PubMed Abstract | Publisher Full Text OpenURL

  66. Mallis RJ, Brazin KN, Fulton DB, Andreotti AH: Structural characterization of a proline-driven conformational switch within the Itk SH2 domain.

    Nat Struct Biol 2002, 9:900-905.

    A further look at the interaction between cyclophilin A and Itk.

    PubMed Abstract | Publisher Full Text OpenURL

  67. Obata Y, Yamamoto K, Miyazaki M, Shimotohno K, Kohno S, Matsuyama T: Role of cyclophilin B in activation of interferon regulatory factor-3.

    J Biol Chem 2005, 280:18355-18360.

    In this study, CypB was shown to interact with IRF-3; it may play a role in IRF-3 activation.

    PubMed Abstract | Publisher Full Text OpenURL

  68. Lin DT, Lechleiter JD: Mitochondrial targeted cyclophilin D protects cells from cell death by peptidyl prolyl isomerization.

    J Biol Chem 2002, 277:31134-31141.

    This study and [70-72] link CypD to mitochondrial permeability transition pores, cell damage, and apoptotic cell death.

    PubMed Abstract | Publisher Full Text OpenURL

  69. Capano M, Virji S, Crompton M: Cyclophilin-A is involved in excitotoxin-induced caspase activation in rat neuronal B50 cells.

    Biochem J 2002, 363:29-36.

    This study presents the evidence that CypA participates in the activation of the caspase cascade in neuronal cells.

    PubMed Abstract | Publisher Full Text OpenURL

  70. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y: Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death.

    Nature 2005, 434:652-658.

    See [68].

    PubMed Abstract | Publisher Full Text OpenURL

  71. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, et al.: Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.

    Nature 2005, 434:658-662.

    See [68].

    PubMed Abstract | Publisher Full Text OpenURL

  72. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P: Properties of the permeability transition pore in mitochondria devoid of cyclophilin D.

    J Biol Chem 2005, 280:18558-18561.

    See [68].

    PubMed Abstract | Publisher Full Text OpenURL