LRRK2
Encyclopedia
Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin, is an enzyme
that in humans is encoded by the LRRK2 gene
. LRRK2 is a member of the leucine-rich repeat
kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease
and also Crohn's disease
.
with an ankyrin repeat
region, a leucine-rich repeat
(LRR) domain, a kinase
domain, a DFG-like motif, a RAS domain, a GTPase domain, an MLK-like domain, and a WD40
domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane
.
LRRK2 interacts with the C-terminal R2 RING finger domain
of parkin
, and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced apoptotic cell death in neuroblastoma cells and in mouse cortical neurons.
s in this gene have been associated with Parkinson's disease
type 8.
The Gly2019Ser mutation in LRRK2 is a relatively common cause of familial Parkinson's Disease in Caucasians. It may also cause sporadic Parkinson's Disease. The mutated Gly amino acid is conserved in all kinase domains of all species.
The Gly2019Ser mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, Gly2019Ser is the most common in the Western World, accounting for ~2% of all Parkinson's disease cases in North American Caucasians. This mutation is enriched in certain populations, being found in approximately 20% of all Ashkenazi Jewish Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of North African Berber Arab ancestry.
Unexpectedly, genomewide association studies have found an association between LRRK2 and Crohn's disease
as well as with Parkinson's disease, suggesting that the two diseases share common pathways.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the LRRK2 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...
. LRRK2 is a member of the leucine-rich repeat
Leucine-rich repeat
A leucine-rich repeat is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine...
kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and also Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
.
Function
The LRRK2 gene encodes a proteinProtein
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...
with an ankyrin repeat
Ankyrin repeat
The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and Drosophila Notch. Ankyrin repeats mediate protein–protein interactions and are among the most common structural motifs in known proteins...
region, a leucine-rich repeat
Leucine-rich repeat
A leucine-rich repeat is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine...
(LRR) domain, a kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
domain, a DFG-like motif, a RAS domain, a GTPase domain, an MLK-like domain, and a WD40
WD40 repeat
The WD40 repeat is a short structural motif of approximately 40 amino acids , often terminating in a tryptophan-aspartic acid dipeptide...
domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane
Outer mitochondrial membrane
thumb|300px|Mitochondria structure :1) [[Inner membrane]]2) Outer membrane3) [[Crista]]4) [[Matrix |Matrix]]The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to the eukaryotic plasma membrane...
.
LRRK2 interacts with the C-terminal R2 RING finger domain
RING finger domain
In molecular biology, a RING finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids...
of parkin
Parkin (ligase)
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...
, and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced apoptotic cell death in neuroblastoma cells and in mouse cortical neurons.
Clinical significance
MutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in this gene have been associated with Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
type 8.
The Gly2019Ser mutation in LRRK2 is a relatively common cause of familial Parkinson's Disease in Caucasians. It may also cause sporadic Parkinson's Disease. The mutated Gly amino acid is conserved in all kinase domains of all species.
The Gly2019Ser mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, Gly2019Ser is the most common in the Western World, accounting for ~2% of all Parkinson's disease cases in North American Caucasians. This mutation is enriched in certain populations, being found in approximately 20% of all Ashkenazi Jewish Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of North African Berber Arab ancestry.
Unexpectedly, genomewide association studies have found an association between LRRK2 and Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
as well as with Parkinson's disease, suggesting that the two diseases share common pathways.