Parkin (ligase)
Encyclopedia
Parkin is a protein
which in humans is encoded by the PARK2 gene
. The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase
complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation
. Mutations in this gene are known to cause a familial form of Parkinson's disease
known as autosomal recessive juvenile Parkinson disease.
How loss of function of the parkin protein leads to dopamine
rgic cell
death in this disease is unclear. The prevailing hypothesis
is that parkin helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of parkin include synphilin-1
, CDC-rel1, cyclin E
, p38 tRNA synthase, Pael-R
, synaptotagmin
XI, sp22 and parkin itself (see also ubiquitin ligase
). Additionally, Parkin contains a C-terminal motif that binds PDZ domain
s. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK
and PICK1
.
Patients with parkin mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
with STUB1
, SEPT5
, Alpha-synuclein
, SNCAIP
, SYT11
, HSPA1A
, Multisynthetase complex auxiliary component p38
, CASK
, CUL1
, PDCD2
, HSPA8, GPR37
, FBXW7
and Ubiquitin C
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the PARK2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. The precise function of this protein is unknown; however, the protein is a component of a multiprotein E3 ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. Mutations in this gene are known to cause a familial form of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
known as autosomal recessive juvenile Parkinson disease.
How loss of function of the parkin protein leads to dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
rgic cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
death in this disease is unclear. The prevailing hypothesis
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
is that parkin helps degrade one or more proteins toxic to dopaminergic neurons. Putative substrates of parkin include synphilin-1
SNCAIP
Synphilin-1 is a protein that in humans is encoded by the SNCAIP gene.-Interactions:SNCAIP has been shown to interact with Alpha-synuclein and Parkin .-Further reading:...
, CDC-rel1, cyclin E
Cyclin E
Cyclin E is a member of the cyclin family.Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase. The Cyclin E/CDK2 complex phosphorylates p27Kip1 , tagging it for degradation, thus promoting expression of Cyclin A, allowing progression to S phase....
, p38 tRNA synthase, Pael-R
GPR37
Probable G-protein coupled receptor 37 is a protein that in humans is encoded by the GPR37 gene.-Interactions:GPR37 has been shown to interact with HSPA1A and Parkin .-Further reading:...
, synaptotagmin
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
XI, sp22 and parkin itself (see also ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
). Additionally, Parkin contains a C-terminal motif that binds PDZ domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
s. Parkin has been shown to associate in a PDZ dependent manner with the PDZ domain containing proteins CASK
CASK
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2 , calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2.-Genomics:This gene is located on the short arm of...
and PICK1
PICK1
PRKCA-binding protein is a protein that in humans is encoded by the PICK1 gene.-Interactions:PICK1 has been shown to interact with HER2/neu, ACCN2, Metabotropic glutamate receptor 7, BNC1, Metabotropic glutamate receptor 3, GRIA4, Dopamine transporter, GRIK1, GRIK2, GRIK3, GRIA2 and GRIA3.-Further...
.
Parkinson's disease
PARK2 (OMIM *602544) is the parkin gene that may cause a form of autosomal recessive juvenile Parkinson disease (OMIM 600116) due to a mutation in the parkin protein. This form of genetic mutation may be one of the most common known genetic causes of early-onset Parkinson disease. In one study of patients with onset of Parkinson disease prior to age 40 (10% of all PD patients), 18% had parkin mutations, with 5% homozygous mutations. Patients with an autosomal recessive family history of parkinsonism are much more likely to carry parkin mutations if age at onset is less than 20 (80% vs. 28% with onset over age 40).Patients with parkin mutations (PARK2) do not have Lewy bodies. Such patients develop a syndrome that closely resembles the sporadic form of PD; however, they tend to develop symptoms at a much younger age.
Interactions
Parkin (ligase) has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with STUB1
STUB1
STUB1 , also known as CHIP , is a human gene.- Function :...
, SEPT5
SEPT5
Septin-5 is a protein that in humans is encoded by the SEPT5 gene.-Interactions:SEPT5 has been shown to interact with SEPT8 and Parkin .-Further reading:...
, Alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...
, SNCAIP
SNCAIP
Synphilin-1 is a protein that in humans is encoded by the SNCAIP gene.-Interactions:SNCAIP has been shown to interact with Alpha-synuclein and Parkin .-Further reading:...
, SYT11
SYT11
Synaptotagmin-11 is a protein that in humans is encoded by the SYT11 gene.-Interactions:SYT11 has been shown to interact with Parkin .-Further reading:...
, HSPA1A
HSPA1A
Heat shock 70 kDa protein 1 is a protein that in humans is encoded by the HSPA1A gene.-Interactions:HSPA1A has been shown to interact with ASK1, STUB1, MSR1, BAG3, Parkin , Fanconi anemia, complementation group C, GPR37, HSF1 and AIFM1....
, Multisynthetase complex auxiliary component p38
Multisynthetase complex auxiliary component p38
Aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 is an enzyme that in humans is encoded by the AIMP2 gene.-Interactions:...
, CASK
CASK
Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2 , calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2.-Genomics:This gene is located on the short arm of...
, CUL1
CUL1
Cullin 1, also known as CUL1, is a human protein and gene from cullin family.This protein plays an important role in protein degradation and protein ubiquitination....
, PDCD2
PDCD2
Programmed cell death protein 2 is a protein that in humans is encoded by the PDCD2 gene.-Interactions:PDCD2 has been shown to interact with Host cell factor C1 and Parkin .-Further reading:...
, HSPA8, GPR37
GPR37
Probable G-protein coupled receptor 37 is a protein that in humans is encoded by the GPR37 gene.-Interactions:GPR37 has been shown to interact with HSPA1A and Parkin .-Further reading:...
, FBXW7
FBXW7
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.-Interactions:FBXW7 has been shown to interact with PPARGC1A, Parkin , MYB and SKP1A.-Further reading:...
and Ubiquitin C
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
.