klotho precursor (KL)
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Function
- weak glycosidase activity towards glucuronylated steroids
- may be inactive as a glycosidase in vivo
- regulation of Ca+2 & phosphorus homeostasis by inhibiting synthesis of 1,25-dihydroxyvitamin D
- essential factor for the specific interaction between FGF23 & FGFR1
- precursor of klotho peptide, a putative anti-aging circulating hormone
Structure
- homodimer
- N-glycosylated
- contains 2 glycosyl hydrolase 1 regions
- the first region lacks the essential Glu active site residue at position 239
- the second region lacks the essential Glu active site residue at position 872
- belongs to the glycosyl hydrolase 1 family, Klotho subfamily
Compartment
- cell membrane, secreted
- insoform 1: cell membrane
- isoform 2: secreted
- klotho peptide: secreted
- secreted form predominates over membrane-bound form in all tissues
Alternative splicing
named isoforms=2
Expression
- expressed in cortical renal tubules
- expressed in brain[3]
- soluble form found in serum & CSF
- expressed in placenta, small intestine, prostate
Pathology
- down-regulated in:
- defects in KL may be a cause of complications in chronic renal failure
- defects in KL are the cause of
Polymorphism
- single copy of KL-VS in ~ 20% of population
- homozygosity for KL-VS allele in ~3% of population[3]
- homozygosity for KL-VS allele is associated with
- decreased longevity
- increased cardiovascular disease risk
- middle-age & older adults who carry a single copy of the KL-VS variant of the KLOTHO Gene perform better on a wide variety of cognitive tests[2]
- a single copy of the KL-VS variant right is associated with a larger dorsolateral prefrontal cortex
- a single copy of KL-VS is associated with reduced risk of Alzheimer's disease & amyloid-beta in cognitively intact elderly 60-80 years who carry APOE4[5]
- G-395A polymorphism in the promoter region of the KLOTHO gene is associated with reduced cognitive impairment in the oldest old[4]
More general terms
- protein precursor
- glycosidase (glycoside hydrolase)
- membrane protein
- glycoprotein
- secreted protein
- human longevity protein
References
- ↑ UniProt http://www.uniprot.org/uniprot/Q9UEF7.html
- ↑ 2.0 2.1 Bioscience and Technology. May 9, 2014 Gladstone Institutes and UC San Francisco
- ↑ 3.0 3.1 3.2 Bioscience and Technology. Jan 28, 2015 Longevity Gene Variant Discovery Gladstone Institutes and UC San Francisco http://www.biosciencetechnology.com/news/2015/01/longevity-gene-variant-discovery
- ↑ 4.0 4.1 Hao Q, Ding X, Gao L, Yang M, Dong B. G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old. AGE. February 2016, 38:7 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26732817
- ↑ 5.0 5.1 Belloy ME, Napolioni V, Han SS et al Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurol. Published online April 13, 2020 PMID: https://www.ncbi.nlm.nih.gov/pubmed/32282020 https://jamanetwork.com/journals/jamaneurology/fullarticle/2763599