scholarly journals IMPDH2 Is an Intracellular Target of the Cyclophilin A and Sanglifehrin A Complex

Cell Reports ◽  
2017 ◽  
Vol 18 (2) ◽  
pp. 432-442 ◽  
Author(s):  
Khian Hong Pua ◽  
Dylan T. Stiles ◽  
Mathew E. Sowa ◽  
Gregory L. Verdine
Keyword(s):  
Cyclophilin A ◽  
Sanglifehrin A ◽  
Intracellular Target

scholarly journals Structure of Human Cyclophilin A in Complex with the Novel Immunosuppressant Sanglifehrin A at 1.6 Å Resolution

2005 ◽  
Vol 280 (23) ◽  
pp. 21965-21971 ◽  
Author(s):  
Joerg Kallen ◽  
Richard Sedrani ◽  
Gerhard Zenke ◽  
Juergen Wagner
Keyword(s):  
Crystal Structure ◽  
Three Dimensional ◽  
Cyclophilin A ◽  
The Other ◽  
Size Exclusion ◽  
Dimensional Structure ◽  
The Novel ◽  
Immunosuppressive Activity ◽  
Exclusion Chromatography ◽  
Sanglifehrin A

Sanglifehrin A (SFA) is a novel immunosuppressant isolated from Streptomyces sp. that binds strongly to the human immunophilin cyclophilin A (CypA). SFA exerts its immunosuppressive activity through a mode of action different from that of all other known immunophilin-binding substances, namely cyclosporine A (CsA), FK506, and rapamycin. We have determined the crystal structure of human CypA in complex with SFA at 1.6 Å resolution. The high resolution of the structure revealed the absolute configuration at all 17 chiral centers of SFA as well as the details of the CypA/SFA interactions. In particular, it was shown that the 22-membered macrocycle of SFA is deeply embedded in the same binding site as CsA and forms six direct hydrogen bonds with CypA. The effector domain of SFA, on the other hand, has a chemical and three-dimensional structure very different from CsA, already strongly suggesting different immunosuppressive mechanisms. Furthermore, two CypA·SFA complexes form a dimer in the crystal as well as in solution as shown by light scattering and size exclusion chromatography experiments. This observation raises the possibility that the dimer of CypA·SFA complexes is the molecular species mediating the immunosuppressive effect.

scholarly journals Cyclophilin A regulates A549 cells apoptosis via stabilizing Twist1 protein

2021 ◽  
Author(s):  
Yaru Wu ◽  
Zhenling Ma ◽  
Yanyan Zhang ◽  
Min Zhang ◽  
Wenwen Zhang ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Intracellular Signaling ◽  
A549 Cells ◽  
Cyclophilin A ◽  
Immunosuppressive Drug ◽  
Nuclear Accumulation ◽  
Biological Processes ◽  
Peptide Bonds ◽  
Intracellular Target

Cyclophilin A (CypA) is an essential member of the immunophilin family. As an intracellular target of immunosuppressive drug cyclosporin A (CsA) or a peptidyl-prolyl cis/trans isomerase (PPIase), it catalyzes the cis-trans isomerization of proline amidic peptide bonds, through which, it regulates a variety of biological processes, such as intracellular signaling, transcription, and apoptosis. In this study, we found that intracellular CypA enhanced Twist1 phosphorylation at Ser68 and inhibited apoptosis in A549 cells. Mechanistically, CypA could mediate the phosphorylation of Twist1 at Ser68 via p38 MAPK, which inhibited its ubiquitination-mediated degradation. In addition, CypA increased Twist–p65 interaction and nuclear accumulation, which regulated Twist1-dependent expression of CDH1 and CDH2. Our findings collectively indicated the role of CypA in Twist1-mediated A549 cells apoptosis through stabilizing Twist1 protein.

Einzelnukleotid-Polymorphismen in der Promotorregion von Cyclophilin A haben keinen EInfluss auf den natürlichen Verlauf einer Hepatitis C Virusinfektion

2013 ◽  
Vol 51 (01) ◽  
Author(s):  
T von Hahn ◽  
B Karavul ◽  
E Steinmann ◽  
A Potthoff ◽  
CP Strassburg ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Cyclophilin A

scholarly journals Cyclophilin A Inhibitor Debio-025 Targets Crk, Reduces Metastasis, and Induces Tumor Immunogenicity in Breast Cancer

2020 ◽  
Vol 18 (8) ◽  
pp. 1189-1201
Author(s):  
Viralkumar Davra ◽  
Tamjeed Saleh ◽  
Ke Geng ◽  
Stanley Kimani ◽  
Dhriti Mehta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cyclophilin A ◽  
Tumor Immunogenicity

scholarly journals APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β

Nature Aging ◽  
2021 ◽  
Vol 1 (6) ◽  
pp. 506-520
Author(s):  
Axel Montagne ◽  
Angeliki M. Nikolakopoulou ◽  
Mikko T. Huuskonen ◽  
Abhay P. Sagare ◽  
Erica J. Lawson ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Cyclophilin A ◽  
Advanced Stage

scholarly journals Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2473
Author(s):  
Jang Mi Han ◽  
Jae Kyung Sohng ◽  
Woo-Haeng Lee ◽  
Tae-Jin Oh ◽  
Hye Jin Jung
Keyword(s):  
Gastric Cancer ◽  
Protein Kinase ◽  
Cancer Progression ◽  
Biological Activities ◽  
Specific Interaction ◽  
Cyclophilin A ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Ags Cells ◽  
In Silico Docking

We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA.

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