Par14 (eukaryotic homolog of parvulin, EHPF) is a member of the

parvulin ] Parvulin, a 92-amino acid protein discovered in E. coli in 1994,Rahfeld JU, Schierhorn A, Mann KH. (1994). A novel peptidyl-prolyl cis/trans isomerase from Escherichia coli. ''FEBS Lett'' 343:65. is the smallest known protein with prolyl isomer ...

family of peptidyl-prolyl-cis/trans-isomerases (PPIases) in humans, which possesses

prolyl isomerase Prolyl isomerase (also known as peptidylprolyl isomerase or PPIase) is an enzyme () found in both prokaryotes and eukaryotes that interconverts the ''cis'' and ''trans'' isomers of peptide bonds with the amino acid proline. Proline has an unusu ...

activity.

History

In 1999, Par14 was identified by two groups independently. After the discovery of human

Pin1 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the ''PIN1'' gene. Pin 1, or peptidyl-prolyl cis/trans isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme bi ...

in 1996, 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 and fails to rescue the loss of the Pin1-related parvulin Ess1 in yeast. 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.

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. The protein is primarily active within the nucleus/nucleolus of the cell, but also found within the cytoplasm.

Biological function

Cytoplasm: Par14 interacts with the insulin receptor substrate (IRS-1) and enhances insulin-induced tyrosine-phosphorylation of IRS-1. During mitosis Par14 associates to the spindle apparatus. ''In vitro'' experiments demonstrated that Par14 may be involved in filament polymerization. Nucleus/Nucleolus: Phosphorylation of Ser19 by

casein kinase 2 Casein kinase 2 ()(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumor ...

translocates Par14 into the cellular nucleus. After dephosphorylation the protein associates to

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...

, with the N-terminus mainly responsible for high-affinity DNA binding. Par14 is found in pre-ribosomal ribonuclear protein complexes, where it acts as an rRNA processing factor.

Photoaffinity labeling Photoaffinity labeling is a chemoproteomics technique used to attach "labels" to the active site of a large molecule, especially a protein. The "label" attaches to the molecule loosely and reversibly, and has an inactive site which can be converted ...

and

Liquid chromatography–mass spectrometry Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography (or HPLC) with the mass analysis capabilities of mass spectrometry (MS). Coupled ...

analysis reveal the enzyme to be associated with proteins functioning in

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inherita ...

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

and/or

chromatin remodeling Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...

. Par14 requires phosphorylation of Ser7 and Ser9 by

protein kinase B Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, t ...

(Akt) (or

protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and ...

) for nuclear export. This export is probably maintained by

14-3-3 14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and tra ...

protein in a

Crm1 Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is a eukaryotic protein that mediates the nuclear export of various proteins and RNAs. History XPO1 (CRM1) originally was identified in the fission yeast ''Schizosaccharom ...

dependent way.

Structure

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. Its three-dimensional structur
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. 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 Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. F ...

virus replication. Expression of Par14 correlates to

primary biliary cirrhosis Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build ...

, an autoimmune chronic cholestatic liver disease. K-RAS exosomes of collateral cancer cells were found to carry Par14.

References

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