Par14 (eukaryotic homolog of parvulin, EHPF) is a member of the parvulin family of peptidyl-prolyl-cis/trans-isomerases (PPIases) in humans, which possesses prolyl isomerase activity.[1]
In 1999, Par14 was identified by two groups independently.[2][3] After the discovery of human Pin1 in 1996,[4] Par14 turned out to be the second member of the human parvulin family. In contrast to Pin1, Par14 exhibits minor catalytic activity, shows no preference for phosphorylated substrates[2] and fails to rescue the loss of the Pin1-related parvulin Ess1 in yeast.[5] Par14 orthologs are found in many unicellular eukaryotes and all multicellular organisms. In 2006, a Par14 isoform, denoted Par17, was described, which carries an N-terminal extension of 25 residues and is exclusively expressed in hominids.[6]
Expression and localization
Par14 originates from transcription of the PIN4 gene on chromosome Xq13.1. The promotor region is TATA-less and located within a CpG island.[6] The protein is primarily active within the nucleus/nucleolus of the cell, but also found within the cytoplasm.[3][4][5][6][7]
Biological function
Cytoplasm: Par14 interacts with the insulin receptor substrate (IRS-1) and enhances insulin-induced tyrosine-phosphorylation of IRS-1.[8] During mitosis Par14 associates to the spindle apparatus.[7]In vitro experiments demonstrated that Par14 may be involved in filament polymerization.[9][10]
Par14’s catalytic domain exhibits the typical parvulin fold (order of secondary structure elements β1-α1-α2-h-β2-α3-β3-β4; α = α-helix, β = β-strand, h = helical turn) found in all members of this family, so far.[16] Its three-dimensional structure PDB-ID: 3UI4 PDB-ID: 1EQ3 is characterized by a ‘gripping hand’ topology with the central β-sheet core (consisting of four antiparallel strands) opposing α-helix 3. The catalytic center resides on the concave side of the β-sheet.[16][17] An N-terminal IDR-like stretch composed of mainly small or basic residues precedes this domain. The IDR element is prone to post-translational modifications.
Disease related function/clinical aspects
Par14 is involved in the upregulation of hepatitis B virus replication.[18] Expression of Par14 correlates to primary biliary cirrhosis, an autoimmune chronic cholestatic liver disease.[19] K-RAS exosomes of collateral cancer cells were found to carry Par14.[20]
↑ Surmacz, Tatiana Anna; Bayer, Elena; Rahfeld, Jens-Ulrich; Fischer, Gunter; Bayer, Peter (2002). "The N-terminal Basic Domain of Human Parvulin hPar14 is Responsible for the Entry to the Nucleus and High-affinity DNA-binding". Journal of Molecular Biology. 321 (2): 235–247. doi:10.1016/s0022-2836(02)00615-0. PMID12144781.
1 2 Sekerina, Elena; Rahfeld, Jens Ulrich; Müller, Jonathan; Fanghänel, Jörg; Rascher, Christine; Fischer, Gunter; Bayer, Peter (2000). "NMR solution structure of h Par14 reveals similarity to the peptidyl prolyl cis/Trans isomerase domain of the mitotic regulator h Pin1 but indicates a different functionality of the protein 1 1Edited by A. Fersht". Journal of Molecular Biology. 301 (4): 1003–1017. doi:10.1006/jmbi.2000.4013. PMID10966801.
↑ Terada, Tohru; Shirouzu, Mikako; Fukumori, Yasuhiro; Fujimori, Fumihiro; Ito, Yutaka; Kigawa, Takanori; Yokoyama, Shigeyuki; Uchida, Takafumi (2001). "Solution structure of the human parvulin-like peptidyl prolyl cis/Trans isomerase, hPar14". Journal of Molecular Biology. 305 (4): 917–926. doi:10.1006/jmbi.2000.4293. PMID11162102.
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