Peptidyl-prolyl cis-trans isomerase A (PPIA)
The protein contains 165 amino acids for an estimated molecular weight of 18012 Da.
Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (PubMed:2001362, PubMed:20676357, PubMed:21245143, PubMed:25678563, PubMed:21593166). Exerts a strong chemotactic effect on leukocytes partly through activation of one of its membrane receptors BSG/CD147, initiating a signaling cascade that culminates in MAPK/ERK activation (PubMed:11943775, PubMed:21245143). Activates endothelial cells (ECs) in a proinflammatory manner by stimulating activation of NF-kappa-B and ERK, JNK and p38 MAP-kinases and by inducing expression of adhesion molecules including SELE and VCAM1 (PubMed:15130913). Induces apoptosis in ECs by promoting the FOXO1-dependent expression of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815). In response to oxidative stress, initiates proapoptotic and antiapoptotic signaling in ECs via activation of NF-kappa-B and AKT1 and up-regulation of antiapoptotic protein BCL2 (PubMed:23180369). Negatively regulates MAP3K5/ASK1 kinase activity, autophosphorylation and oxidative stress-induced apoptosis mediated by MAP3K5/ASK1 (PubMed:26095851). Necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and regulates TARDBP binding to RNA UG repeats and TARDBP-dependent expression of HDAC6, ATG7 and VCP which are involved in clearance of protein aggregates (PubMed:25678563). Plays an important role in platelet activation and aggregation (By similarity). Regulates calc (updated: Oct. 7, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
Activation of MAPK activity
Activation of protein kinase B activity
Apoptotic process
Blood coagulation
Cell adhesion molecule production
Cellular response to oxidative stress
Endothelial cell activation
Entry into host
Entry into host cell
Establishment of integrated proviral latency
Fusion of virus membrane with host plasma membrane
Interleukin-12-mediated signaling pathway
Leukocyte chemotaxis
Leukocyte migration
Lipid droplet organization
Negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
Negative regulation of protein K48-linked ubiquitination
Negative regulation of protein kinase activity
Negative regulation of protein phosphorylation
Negative regulation of stress-activated MAPK cascade
Negative regulation of viral life cycle
Neutrophil chemotaxis
Neutrophil degranulation
Platelet activation
Platelet aggregation
Platelet degranulation
Positive regulation of NF-kappaB transcription factor activity
Positive regulation of protein dephosphorylation
Positive regulation of protein phosphorylation
Positive regulation of protein secretion
Positive regulation of viral genome replication
Protein folding
Protein peptidyl-prolyl isomerization
Protein refolding
Regulation of apoptotic signaling pathway
Regulation of viral genome replication
RNA-dependent DNA biosynthetic process
Uncoating of virus
Viral life cycle
Viral process
Viral release from host cell
Virion assembly
The reference OMIM entry for this protein is 123840
Peptidyl-prolyl isomerase a; ppia
Cyclophilin a; cypa
Cyph
CLONING
Cyclophilin is a specific high-affinity binding protein for the immunosuppressant agent cyclosporin A. Because of its dramatic effects on decreasing morbidity and increasing survival rates in human transplants, the molecular mechanism of immunosuppression by cyclosporin A has been a matter of much interest. Liu et al. (1990) cloned human cDNA for T-cell CYPH and constructed an expression vector under control of the tac promoter for efficient expression in E. coli.GENE FUNCTION
Cyclophilin A (also designated peptidyl-prolyl cis/trans isomerase A or PPIA) is a member of the immunophilin class of proteins that all possess peptidyl-prolyl cis/trans isomerase activity and, therefore, are believed to be involved in protein folding and/or intracellular protein transport. Luban et al. (1993) showed that cyclophilin A binds to the Gag protein of human immunodeficiency virus type 1 (HIV-1). This interaction can be inhibited by the immunosuppressant cyclosporin A and also by nonimmunosuppressive, cyclophilin A-binding cyclosporin A derivatives, which were also shown to exhibit potent anti-HIV-1 activity. Thus, cyclophilin A may have an essential function in HIV-1 replication. Pushkarsky et al. (2001) identified CD147 (BSG; 109480) as a receptor for extracellular CYPA. They found that CD147 enhanced HIV-1 infection through interaction with CYPA incorporated into virions. Virus-associated CYPA coimmunoprecipitated with CD147 from infected cells, and antibody to CD147 inhibited HIV-1 entry. Viruses whose replication did not require CYPA were resistant to the inhibitory effect of anti-CD147 antibody. Pushkarsky et al. (2001) concluded that HIV-1 entry depends on an interaction between virus-associated CYPA and CD147 on a target cell. Towers et al. (2003) demonstrated that HIV-1 sensitivity to restriction factors is modulated by CYPA. In certain nonhuman primate cells, the HIV-1 capsid protein (CA)-CYPA interaction is essential for restriction: HIV-1 infectivity is increased greater than 100-fold by cyclosporin A, a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CYPA binding. Conversely, disruption of CA-CYPA interaction in human cells reveals that CYPA protects HIV-1 from the Ref-1 restriction factor. Towers et al. (2003) concluded that their findings suggest that HIV-1 has coopted a host cell protein to counteract restriction factors expressed by human cells and this adaptation can confer sensitivity to restriction in unnatural hosts. Manel et al. (2010) showed that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response, and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3 (603734). Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, the results of Manel et al. (2010) indicated that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. Using different Apoe (107741) transgenic mice, including mice with ablation and/or inhibition of CypA, Bell et al. (2012) showe ... More on the omim web site
Oct. 20, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 123840 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed