title: Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.
abstract: Cyclophilins are peptidyl cis-trans prolyl isomerases (PPIases), whose activity is typically inhibited by cyclosporine A (CsA), a potent immunosuppressor. Cyclophilins are also chaperones. Emerging evidence supports that cyclophilins present nonoverlapping PPIase and chaperone activities. The proteostasis of the disease-relevant substrates, signal transducer and activator of transcription 3 and 5 (STAT3/STAT5), heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), and M-opsin, is regulated by nonoverlapping chaperone and PPIase activities of the cyclophilin domain (CY) of Ranbp2, a multifunctional and modular scaffold that controls nucleocytoplasmic shuttling and proteostasis of selective substrates. Although highly homologous, CY and the archetypal cyclophilin A (CyPA) present distinct catalytic and CsA-binding activities owing to unique structural features between these cylophilins. We explored structural idiosyncrasies between CY and CyPA to screen in silico nearly 9 million small molecules (SM) against the CY PPIase pocket and identify SMs with selective bioactivity toward STAT3, hnRNPA2B1, or M-opsin proteostasis. We found three classes of SMs that enhance the cytokine-stimulated transcriptional activity of STAT3 without changing latent and activated STAT3 levels, down-regulate hnRNPA2B1 or M-opsin proteostasis, or a combination of these. Further, a SM that suppresses hnRNPA2B1 proteostasis also inhibits strongly and selectively the PPIase activity of CY. This study unravels chemical probes for multimodal regulation of CY of Ranbp2 and its substrates, and this regulation likely results in the allosterism stemming from the interconversion of conformational substates of cyclophilins. The results also demonstrate the feasibility of CY in drug discovery against disease-relevant substrates controlled by Ranbp2, and they open new opportunities for therapeutic interventions.
authors.affiliation: †Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina 27710, United States.
authors.forename: Kyoung-In
authors.initials: KI
authors.lastname: Cho
authors.affiliation: ‡MolSoft LLC, San Diego, California 92121, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Orry
authors.affiliation: †Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina 27710, United States.
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: †Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina 27710, United States.|§Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, United States.
authors.forename: Paulo A
authors.initials: PA
authors.lastname: Ferreira
mesh_terms: D000595:Amino Acid Sequence; D021984:Cyclophilin A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055355:Opsins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D008024:Ligands; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D055355:Opsins; D050796:STAT3 Transcription Factor; C439768:hnRNP A2; C094493:ran-binding protein 2; D021984:Cyclophilin A
keywords: M-opsin; Ran-binding protein 2 (Ranbp2); STAT3; chaperone; chemical ligands; cyclophilin; hnRNPA2B1; proteostasis