Biology:UNC13A
 Generic protein structure example |
Unc-13 homolog A (C. elegans) is a protein that in humans is encoded by the UNC13A gene.[1]
Function
This gene encodes a member of the UNC13 family.[1] UNC13A plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. It is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool. In Drosophila melanogaster, the protein has been shown to define the vesicle release site by regulating the coupling distance between synaptic vesicles and calcium channels in cooperation with another isoform, UNC13B.[2] It is particularly important in most glutamatergic-mediated synapses as well as GABA-mediated synapses. It plays a role in dendrite formation by melanocytes and in secretory granule priming in insulin secretion.[3]
Protein structure
Several conserved domains have been found in UNC13A. These conserved domains include three C2 domains. One C2 domain is centrally located, another is at the carboxyl end, and there is a third. In addition, there is one C1 domain, as well as Munc13 homology domains 1 (MHD1) and 2 (MHD2).[3][4]
Subcellular location
UNC13A is localized to the active zone of presynaptic density. It is translocated to the plasma membrane in response to phorbol ester binding.[3]
Interaction
UNC13A has been shown to interact with:
Clinical significance
Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis.[5][6][7][8] This single nucleotide polymorphism has been discovered on chromosome 19. This variation of the single nucleotide involving UNC13A has also been implicated in frontotemporal dementia (FTD). Pathology of TDP-43 in both ALS and FTD results in a cryptic exon being expressed in UNC13A, which is exercerbated by the single nucleotide polymorphisms associated with ALS and FTD risk.[9][10][11] This gene has also been associated with Alzheimer's disease (AD).[12]
References
- ↑ 1.0 1.1 "Entrez Gene: Unc-13 homolog A (C. elegant)". https://www.ncbi.nlm.nih.gov/gene/23025.
- ↑ "Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca(2+) channel-vesicle coupling". Nature Neuroscience 19 (10): 1311–1320. October 2016. doi:10.1038/nn.4364. PMID 27526206.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 "UNC13A - Protein unc-13 homolog A - Homo sapiens (Human) - UNC13A gene & protein". https://www.uniprot.org/uniprot/Q9UPW8.
- ↑ "NCBI Conserved Domain Search". https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi?seqinput=NP_001073890.2.
- ↑ "Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis". Nature Genetics 41 (10): 1083–1087. October 2009. doi:10.1038/ng.442. PMID 19734901.
- ↑ "Genetic determinants of amyotrophic lateral sclerosis as therapeutic targets". CNS & Neurological Disorders Drug Targets 9 (6): 779–790. December 2010. doi:10.2174/187152710793237494. PMID 20942785.
- ↑ "Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research". Muscle & Nerve 49 (6): 786–803. June 2014. doi:10.1002/mus.24198. PMID 24488689.
- ↑ "Recent progress in the genetics of motor neuron disease". European Journal of Medical Genetics 57 (2–3): 103–112. February 2014. doi:10.1016/j.ejmg.2014.01.002. PMID 24503148.
- ↑ "TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A". Nature 603 (7899): 124–130. March 2022. doi:10.1038/s41586-022-04424-7. PMID 35197626. Bibcode: 2022Natur.603..124M.
- ↑ "TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A". Nature 603 (7899): 131–137. March 2022. doi:10.1038/s41586-022-04436-3. PMID 35197628. Bibcode: 2022Natur.603..131B.
- ↑ "C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis". Annals of Neurology 76 (1): 120–133. July 2014. doi:10.1002/ana.24198. PMID 24931836.
- ↑ "Munc13 genotype regulates secretory amyloid precursor protein processing via postsynaptic glutamate receptors". International Journal of Developmental Neuroscience 31 (1): 36–45. February 2013. doi:10.1016/j.ijdevneu.2012.10.001. PMID 23070049.
Further reading
- "Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles". Nature 400 (6743): 457–461. July 1999. doi:10.1038/22768. PMID 10440375. Bibcode: 1999Natur.400..457A.
- "Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release". Neuron 21 (1): 123–136. July 1998. doi:10.1016/s0896-6273(00)80520-6. PMID 9697857.
- "Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming". Neuron 30 (1): 183–196. April 2001. doi:10.1016/s0896-6273(01)00272-0. PMID 11343654.
- "Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1". Traffic 12 (10): 1356–1370. October 2011. doi:10.1111/j.1600-0854.2011.01237.x. PMID 21689256.
- "Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform". The Biochemical Journal 349 (Pt 1): 247–253. July 2000. doi:10.1042/0264-6021:3490247. PMID 10861235.
- "DOC2B and Munc13-1 differentially regulate neuronal network activity". Cerebral Cortex 24 (9): 2309–2323. September 2014. doi:10.1093/cercor/bht081. PMID 23537531.
- "Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1". The Journal of Cell Biology 158 (3): 577–590. August 2002. doi:10.1083/jcb.200202083. PMID 12163476.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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