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Structural and Functional Insights Into Human Nuclear Cyclophilins

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Structural and Functional Insights Into Human Nuclear Cyclophilins biomolecules Review Structural and Functional Insights into Human Nuclear Cyclophilins Caroline Rajiv 1,2 and Tara L. Davis 1,3,* 1 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; [email protected] 2 Janssen Pharmaceuticals Inc., 22-21062, 1400 McKean Rd, Spring House, PA 19477, USA 3 FORMA Therapeutics, 550 Arsenal St. Ste. 100, Boston, MA 02472, USA * Correspondence: [email protected]; Tel.: +1-857-209-2342 Received: 31 October 2018; Accepted: 22 November 2018; Published: 4 December 2018 Abstract: The peptidyl prolyl isomerases (PPI) of the cyclophilin type are distributed throughout human cells, including eight found solely in the nucleus. Nuclear cyclophilins are involved in complexes that regulate chromatin modification, transcription, and pre-mRNA splicing. This review collects what is known about the eight human nuclear cyclophilins: peptidyl prolyl isomerase H (PPIH), peptidyl prolyl isomerase E (PPIE), peptidyl prolyl isomerase-like 1 (PPIL1), peptidyl prolyl isomerase-like 2 (PPIL2), peptidyl prolyl isomerase-like 3 (PPIL3), peptidyl prolyl isomerase G (PPIG), spliceosome-associated protein CWC27 homolog (CWC27), and peptidyl prolyl isomerase domain and WD repeat-containing protein 1 (PPWD1). Each “spliceophilin” is evaluated in relation to the spliceosomal complex in which it has been studied, and current work studying the biological roles of these cyclophilins in the nucleus are discussed. The eight human splicing complexes available in the Protein Data Bank (PDB) are analyzed from the viewpoint of the human spliceophilins. Future directions in structural and cellular biology, and the importance of developing spliceophilin-specific inhibitors, are considered. Keywords: peptidyl prolyl isomerases; nuclear cyclophilins; spliceophilins; alternative splicing; spliceosomes; NMR; X-ray crystallography 1. Introduction Cyclophilins are members of the peptidyl prolyl isomerase (PPI) family, along with the structurally unrelated FK506 binding proteins and the parvulins (EC 5.2.1) [1–3]. Cyclophilins are evolutionarily widespread, with paralog cyclophilins found in all kingdoms of life, including viruses. In many species, there exist multiple cyclophilins encoded in the genome; depending on how strictly one defines a sequence as cyclophilin-like, there are anywhere from 17 to 30 cyclophilins encoded in humans [1,2,4]. In humans, as in other multicellular organisms, when multiple cyclophilin family members are encoded, they are also often found targeted to multiple cellular compartments. One family member, peptidyl prolyl isomerase F (PPIF), is targeted to mitochondria, where it participates in the regulation of the mitochondrial permeability transition pore [5–7]. The three cytoplasmic cyclophilins—the canonical family member peptidyl prolyl isomerase A (PPIA), plus peptidyl prolyl isomerase B (PPIB) and peptidyl prolyl isomerase C (PPIC)—have also been detected extracellularly in various reports. These studies have focused on the mechanisms by which these three cyclophilins facilitate host: viral interactions, particularly for human immunodeficiency virus (HIV) and hepatitis A, B, and C viruses [8–10]. Much less is known about the cytoplasmic cyclophilins peptidyl prolyl isomerase D (PPID), peptidyl prolyl isomerase-like 4 (PPIL4), RAN binding protein 2 (RANBP2), and the nuclear cyclophilins peptidyl prolyl isomerase-like 4 (PPIL6) and natural killer cell triggering receptor (NKTR), Biomolecules 2018, 8, 161; doi:10.3390/biom8040161 www.mdpi.com/journal/biomolecules Biomolecules 2018, 8, 161 2 of 26 andBiomolecules these will2018, 8 not, 161 be discussed further here. The purpose of this review is to highlight2 of what 26 is currently known about the structure and biological function of the eight human nuclear-localized cyclophilins: receptor (NKTR), and these will not be discussed further here. The purpose of this review is to peptidylhighlight prolylwhat is isomerase currently known E (PPIE), about peptidyl the structure prolyl and isomerase biological Gfunction (PPIG), of peptidylthe eight human prolyl isomerase H (PPIH),nuclear- peptidyllocalized cyclophilins: prolyl isomerase-like peptidyl prol 1yl (PPIL1), isomerase peptidyl E (PPIE prolyl), peptidyl isomerase-like prolyl isomerase 2 (PPIL2), G peptidyl prolyl(PPIG isomerase-like), peptidyl prolyl 3isomerase (PPIL3), H peptidyl (PPIH), peptidyl prolyl isomeraseprolyl isomerase domain-like and1 (PPIL1 WD), peptidyl repeat-containing prolyl protein 1 (PPWD1),isomerase- andlike 2 spliceosome-associated (PPIL2), peptidyl prolyl isomerase protein-like CWC27 3 (PPIL3 homolog), peptidyl (CWC27). prolyl isomerase domain and CyclophilinsWD repeat-containing are characterized protein 1 (PPWD1 by) a, and central spliceosome closed-associated barrel type protein beta CWC27 fold, withhomolog large regions of (CWC27). ordered loops and two small helices packed against the loop region and sheets β7–β8 of the central Cyclophilins are characterized by a central closed barrel type beta fold, with large regions of barrelordered (structural loops and two classification small helices of packed proteins against (SCOP) the loop fold region family and 50892). sheets β7 See–β8 Figureof the central1 for the structure ofbarrel the canonical(structural c familylassification member of proteins PPIA. (SCOP) There fold is afamily high 50892). degree See of Figure sequence 1 for andthe structure structural similarity acrossof the thecanonical entire family cyclophilin member family,PPIA. There which is a has high been degree discussed of sequence elsewhere and structural [1,3, 4similarity]. A simple sequence alignmentacross the entire comparing cyclophilin the family, isomerase which domains has been ofdiscussed the eight elsewhere nuclear [1,3,4] cyclophilins. A simple tosequence PPIA, along with a alignment comparing the isomerase domains of the eight nuclear cyclophilins to PPIA, along with a structure-based alignment, is shown in Supplementary Figure S1. structure-based alignment, is shown in Supplementary Figure S1. PPIA PPIA 55 60 61 63 101 113 121 122 126 73 81 82 103 107 110 111 residue residue PPIA Arg Phe Met Gln Ala Phe Trp Leu His PPIA Thr Glu Lys Ala Thr Ser Gln PPIE Arg Phe Met Gln Ala Phe Trp Leu His PPIE Thr Lys Lys Ser Thr Ser Gln PPIG Arg Phe Met Gln Ala Phe His Leu His PPIG Arg Gly Phe Arg Thr Ser Gln PPIH Arg Phe Met Gln Ala Phe Trp Leu His PPIH Thr Gly Pro Ser Thr Cys Gln PPIL1 Arg Phe Met Gln Ala Phe Trp Leu His PPIL1 Thr Lys Gln Ala Thr Ser Gln PPIL2 Arg Phe Val Gln Ala Phe Tyr Leu His PPIL2 Thr Lys Pro Ser Ser Ser Gln PPIL3 Arg Phe Met Gln Ala Phe His Leu Tyr PPIL3 Arg Lys Lys Asn Thr Ser Gln PPWD1 Arg Phe Met Gln Ala Phe Trp Leu His PPWD1 Met Gly Glu Ala Thr Ser Gln CWC27 Arg Phe Ile Gln Ala Phe Glu Leu His CWC27 Ser Ala Pro Ala Asp Ser Gln Figure 1. Structure and annotation of the canonical cyclophilin PPIA. (A) Left panel, secondary Figure 1. Structure and annotation of the canonical cyclophilin PPIA. (A) Left panel, secondary structural elements are labeled for the PDB ID: 2CPL. Right panel, residues that comprise the S1 structural(proline-binding) elements and S2 are (specificity) labeled pockets for the are PDB shown ID: in 2CPL. stick representation Right panel, and residues labeled. S1 that pocket comprise the S1 (proline-binding)labels are on the right, and S2 S2pocket (specificity) labels on the pockets left, and are in bold shown are residues in stick invariant representation across the and nuclear labeled. S1 pocket labelscyclophilin are onfamily. the Residue right, S2 numbering pocket labelsalso follows on the PPIA, left, by and convention. in bold are(B) The residues residues invariant that across the nuclearcomprise cyclophilin the S1 pockets family. are largely Residue invariant, numbering while (C also) the followsresidues PPIA,that comprise by convention. the S2 pockets (B) are The residues that comprisemore variable. the S1 pockets are largely invariant, while (C) the residues that comprise the S2 pockets are more variable. Additionally, many cyclophilin family members in more complex organisms encode for additional motifs and domains (see Figure 2), discussed in further detail below for the human nuclear Additionally, many cyclophilin family members in more complex organisms encode for additional motifs and domains (see Figure2), discussed in further detail below for the human nuclear cyclophilins PPIE, PPIG, PPIL2, PPWD1, and CWC27. Originally characterized as the protein receptor for the natural product cyclosporine, cyclophilins have long been studied in vitro because of their high solubility and attractive biophysical properties. Decades of structural work utilizing well-behaved Biomolecules 2018, 8, 161 3 of 26 cyclophilinsBiomolecules 2018 PPIE,, 8, 161 PPIG, PPIL2, PPWD1, and CWC27. Originally characterized as the protein3 of 26 receptor for the natural product cyclosporine, cyclophilins have long been studied in vitro because of their high solubility and attractive biophysical properties. Decades of structural work utilizing well-behavedcyclophilins have cyclophilins led to nearly have led complete to nearly coverage complete of thecoverage human of cyclophilinthe human cyclophilin family, by bothfamily, X-ray by bothcrystallography X-ray crystallography and nuclear and magnetic nuclear resonance magnetic (NMR) resonance [1,11 –(NMR)15]. These [1,11–15]. structures These have structures been used have to beenfacilitate used studies to facilitate focused onstudies
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