Parvulin 14

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]

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]

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]

Nucleus/Nucleolus: Phosphorylation of Ser19 by casein kinase 2 translocates Par14 into the cellular nucleus.[11] After dephosphorylation the protein associates to chromatin,[12] with the N-terminus mainly responsible for high-affinity DNA binding.[13] Par14 is found in pre-ribosomal ribonuclear protein complexes, where it acts as an rRNA processing factor.[7][14] Photoaffinity labeling and Liquid chromatography–mass spectrometry analysis reveal the enzyme to be associated with proteins functioning in DNA replication, DNA repair and/or chromatin remodeling.[10] Par14 requires phosphorylation of Ser7 and Ser9 by protein kinase B (Akt) (or protein kinase C) for nuclear export. This export is probably maintained by 14-3-3 protein in a Crm1 dependent way.[15]

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.

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]