PPIA

Official Full Name

peptidylprolyl isomerase A

Organism

Homo sapiens

GeneID

5478

Background

This gene encodes a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. The encoded protein is a cyclosporin binding-protein and may play a role in cyclosporin A-mediated immunosuppression. The protein can also interact with several HIV proteins, including p55 gag, Vpr, and capsid protein, and has been shown to be necessary for the formation of infectious HIV virions. Multiple pseudogenes that map to different chromosomes have been reported. [provided by RefSeq, Jul 2008]

Synonyms

CYPA; CYPH; HEL-S-69p;

Bio Chemical Class

Cis-trans-isomerases

Protein Sequence

MVNPTVFFDIAVDGEPLGRVSFELFADKVPKTAENFRALSTGEKGFGYKGSCFHRIIPGFMCQGGDFTRHNGTGGKSIYGEKFEDENFILKHTGPGILSMANAGPNTNGSQFFICTAKTEWLDGKHVVFGKVKEGMNIVEAMERFGSRNGKTSKKITIADCGQLE

Open

Disease

Nutritional deficiency

Approved Drug

1 +

Clinical Trial Drug

Discontinued Drug

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Detailed Information

The PPIA (peptidyl-prolyl cis-trans isomerase A) gene is located on human chromosome 7p13, containing five exons and encoding a cytosolic protein of 165 amino acids with a molecular weight of 18 kDa. The protein belongs to the cyclophilin subfamily of immunophilins and features an eight-stranded β-barrel fold forming a hydrophobic cavity critical for catalytic activity and immunosuppressant binding. Its active site contains highly conserved residues, including Arg55, Phe60, Phe113, and Trp121, which mediate substrate recognition and catalysis. The enzymatic mechanism stabilizes a distorted tetrahedral transition state, reducing the activation energy of cis-trans isomerization at prolyl peptide bonds and thereby accelerating protein folding.

Figure 1. Structure of CypA showing its β-barrel fold and the binding of CsA at the PPIase active site. (Han JM, et al., 2022)

Expression and Evolution

PPIA is expressed ubiquitously, with the highest levels found in the thymus, spleen, and hematopoietic tissues, reflecting its essential role in cellular homeostasis. Multiple transcript variants exist but encode the same protein, suggesting regulation occurs primarily at the post-transcriptional level. Evolutionarily, PPIA is highly conserved, with over 60% sequence identity to yeast cyclophilin, underscoring its indispensable function. In addition to the functional gene, several pseudogenes such as PPIAL4C exist, potentially contributing to transcriptional regulation.

Biological Functions

PPIA catalyzes the cis-trans isomerization of prolyl peptide bonds, a key rate-limiting step in protein folding. Accelerating this process ensures efficient and correct folding of a wide spectrum of substrates, particularly hydrophobic or aromatic proline-containing sequences. Beyond its foldase role, PPIA acts as a molecular chaperone, preventing misfolding and aggregation, especially under stress conditions such as heat shock or oxidative damage.

Recent work has shown that PPIA plays a central role in hematopoietic stem cell homeostasis. It preferentially interacts with intrinsically disordered proteins involved in stress granules, P-bodies, and nucleoli, promoting liquid–liquid phase separation and stress resistance. Loss of PPIA disrupts these networks, leading to impaired stress response and accelerated stem cell aging.

PPIA also exerts extracellular functions through interaction with CD147 (Basigin), triggering ERK/MAPK and NF-κB signaling cascades. This mediates chemotaxis, inflammation, and platelet activation, highlighting its dual role as both a cytoprotective chaperone and a pro-inflammatory mediator depending on cellular context.

Role in Disease

PPIA contributes to viral pathogenesis by supporting HIV-1 capsid stability, enhancing HCV replication through NS5A interaction, and modulating influenza A virus replication. In aging, reduced PPIA expression contributes to hematopoietic stem cell decline, while in cancers such as hepatocellular carcinoma and glioblastoma, its overexpression drives tumor growth, hypoxia adaptation, and resistance to apoptosis. Elevated extracellular PPIA has also been linked to autoimmune and inflammatory diseases, including rheumatoid arthritis and atherosclerosis, where it amplifies inflammatory cascades.

Therapeutic Prospects

As a therapeutic target, PPIA inhibition has been most explored in antiviral and cancer settings. The classical inhibitor cyclosporin A blocks PPIA activity but is limited by immunosuppressive toxicity. Newer non-immunosuppressive analogs, such as NIM811 and Alisporivir, have shown promise in HCV and COVID-19 trials. Beyond antivirals, experimental inhibitors and monoclonal antibodies targeting the PPIA–CD147 axis are being developed for inflammatory diseases, fibrosis, and cancer. Early studies also suggest potential applications in neuroprotection and tumor immunotherapy.

Future therapeutic advances will require improved tissue-specific targeting, better separation of intracellular protective versus extracellular pathogenic roles, and integration of PPIA-related biomarkers to guide personalized treatment strategies.

Reference

Schiene-Fischer C, Fischer G, Braun M. Non-Immunosuppressive Cyclophilin Inhibitors. Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202201597.
Han JM, Jung HJ. Cyclophilin A/CD147 Interaction: A Promising Target for Anticancer Therapy. Int J Mol Sci. 2022 Aug 19;23(16):9341.

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