Protein deglycase DJ-1, also known as Parkinson disease protein 7, is a protein which in humans is encoded by the PARK7 gene. [5]
Protein deglycase DJ-1, also known as Parkinson disease protein 7, is a protein which in humans is encoded by the PARK7 gene. [5]
The gene PARK7, also known as DJ-1, encodes a protein of the peptidase C56 family. The human gene PARK7 has 8 exons and locates at chromosome band 1p36.23. [5]
The human protein deglycase DJ-1 is 20 kDa in size and composed of 189 amino acids with seven β-strands and nine α-helices in total and is present as a dimer. [6] [7] [8] It belongs to the peptidase C56 family of proteins.
The protein structures of human protein DJ-1, Escherichia coli chaperone Hsp31, YhbO, and YajL and an Archaea protease are evolutionarily conserved. [9]
Under an oxidative condition, protein deglycase DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity, [10] [11] thus functioning as a redox-sensitive chaperone and as a sensor for oxidative stress. Accordingly, DJ-1 apparently protects neurons against oxidative stress and cell death. [5] In parallel, protein DJ-1 acts as a positive regulator of androgen receptor-dependent transcription. DJ-1 is expressed in both the neural retina and retinal pigment epithelium of mammals, where it exerts a neuroprotective role against oxidative stress under both physiological and pathological conditions. [12] [13]
Pyrroloquinoline quinone (PQQ) has been shown to reduce the self-oxidation of the DJ-1 protein, an early step in the onset of some forms of Parkinson's disease. [14]
Functional DJ-1 protein has been shown to bind metals and protect against metal-induced cytotoxicity from copper and mercury. [15]
DJ-1/PARK7 and its bacterial homologs: Hsp31, YhbO, and YajL can repair methylglyoxal and glyoxal glycated nucleotides. [16] Guanine, either in the form of a free nucleotide or as a nucleotide incorporated into nucleic acid (DNA or RNA), if glycated, can be repaired by DJ-1/PARK7. [16] Deglycase-deficient bacterial mutants with reduced ability to repair glycated bases in DNA show strong mutator phenotypes. [16]
DJ-1 is a DNA damage response protein that is recruited to sites of DNA damage where it participates in the repair of DNA double-strand breaks through the processes of non-homologous end joining and homologous recombination. [17] Evidence for a linkage between DNA damage and Parkinson's disease has been reported for decades. [17] Recently evidence has been presented that defective DNA repair is linked specifically to DJ-1 mutation, and thus DJ-1 mutation likely contributes to Parkinson's disease pathogenesis. [17]
Defects in this gene are the cause of autosomal recessive early-onset Parkinson's disease 7. [5] [18]
PARK7 has been shown to interact with:
Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).
Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.
Human gene HSPA1B is an intron-less gene which encodes for the heat shock protein HSP70-2, a member of the Hsp70 family of proteins. The gene is located in the major histocompatibility complex, on the short arm of chromosome 6, in a cluster with two paralogous genes, HSPA1A and HSPA1L. HSPA1A and HSPA1B produce nearly identical proteins because the few differences in their DNA sequences are almost exclusively synonymous substitutions or in the three prime untranslated region, heat shock 70kDa protein 1A, from HSPA1A, and heat shock 70kDa protein 1B, from HSPA1B. A third, more modified paralog to these genes exists in the same region, HSPA1L, which shares a 90% homology with the other two.
Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.
Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ILF3 gene.
E3 SUMO-protein ligase PIAS2 is an enzyme that in humans is encoded by the PIAS2 gene.
DnaJ homolog subfamily B member 1 is a protein that in humans is encoded by the DNAJB1 gene.
Sterol O-acyltransferase 1, also known as SOAT1, is an enzyme that in humans is encoded by the SOAT1 gene.
Nuclear transcription factor Y subunit gamma is a protein that in humans is encoded by the NFYC gene.
A kinase anchor protein 1, mitochondrial is an enzyme that in humans is encoded by the AKAP1 gene.
F-box only protein 7 is a protein that in humans is encoded by the FBXO7 gene. Mutations in FBXO7 have been associated with Parkinson's disease.
A-kinase anchor protein 8 is an enzyme that, in humans, is encoded by the AKAP8 gene.
Probable cation-transporting ATPase 13A2 is an enzyme that in humans is encoded by the ATP13A2 gene that is involved in the transport of divalent transition metal cations. It appears to protect cells from manganese and zinc toxicity, possibly by causing cellular efflux and/or lysosomal sequestration; and from iron toxicity, possibly by preserving lysosome integrity against iron-induced lipid peroxidation. However, it potentiates the toxic effects of cadmium and nickel on developing neurites, and of the widely used herbicide paraquat possibly by increasing polyamine uptake.
Prefoldin subunit 5 is a protein that in humans is encoded by the PFDN5 gene.
C-Myc-binding protein is a protein that in humans is encoded by the MYCBP gene.
EF-hand calcium-binding domain-containing protein 6 is a protein that in humans is encoded by the EFCAB6 gene.
AMY-1-associating protein expressed in testis 1 is a protein that in humans is encoded by the MAATS1 gene.
NDUFA4, mitochondrial complex associated is a protein that in humans is encoded by the NDUFA4 gene. The NDUFA4 protein was first described to be a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. However, recent research has described NDUFA4 as a subunit of cytochrome c oxidase. Mutations in the NDUFA4 gene are associated with Leigh's syndrome.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
