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Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.

Publication ,  Journal Article
Cho, K-I; Orry, A; Park, SE; Ferreira, PA
Published in: ACS Chem Neurosci
August 19, 2015

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.

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Published In

ACS Chem Neurosci

DOI

EISSN

1948-7193

Publication Date

August 19, 2015

Volume

6

Issue

8

Start / End Page

1476 / 1485

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • STAT3 Transcription Factor
  • Opsins
  • Nuclear Pore Complex Proteins
  • Molecular Structure
  • Molecular Sequence Data
  • Molecular Chaperones
  • Ligands
  • Humans
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
 

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Cho, K.-I., Orry, A., Park, S. E., & Ferreira, P. A. (2015). Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin. ACS Chem Neurosci, 6(8), 1476–1485. https://doi.org/10.1021/acschemneuro.5b00134
Cho, Kyoung-In, Andrew Orry, Se Eun Park, and Paulo A. Ferreira. “Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.ACS Chem Neurosci 6, no. 8 (August 19, 2015): 1476–85. https://doi.org/10.1021/acschemneuro.5b00134.
Cho, Kyoung-In, et al. “Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-opsin.ACS Chem Neurosci, vol. 6, no. 8, Aug. 2015, pp. 1476–85. Pubmed, doi:10.1021/acschemneuro.5b00134.
Journal cover image

Published In

ACS Chem Neurosci

DOI

EISSN

1948-7193

Publication Date

August 19, 2015

Volume

6

Issue

8

Start / End Page

1476 / 1485

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • STAT3 Transcription Factor
  • Opsins
  • Nuclear Pore Complex Proteins
  • Molecular Structure
  • Molecular Sequence Data
  • Molecular Chaperones
  • Ligands
  • Humans
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B