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klotho precursor (KL)

Function: 1) weak glycosidase activity towards glucuronylated steroids - may be inactive as a glycosidase in vivo 2) regulation of Ca+2 & phosphorus homeostasis by inhibiting synthesis of 1,25-dihydroxyvitamin D 3) essential factor for the specific interaction between FGF23 & FGFR1 4) 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 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 a) decreased longevity b) 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] Pathology: - down-regulated in: a) renal cell carcinomas b) hepatocellular carcinomas c) chronic renal failure kidney - defects in KL may be a cause of complications in chronic renal failure - defects in KL are the cause of - hyperphosphatemic familial tumoral calcinosis

General

glycoprotein glycosidase (glycoside hydrolase) human longevity protein membrane protein protein precursor secreted protein

Properties

SIZE: MW = 116 kD entity length = 1012 aa COMPARTMENT: cellular membrane MOTIF: signal sequence {1-33} Glycosyl hydrolase-1 1 {57-506} MOTIF: N-glycosylation site {N106} N-glycosylation site {N159} N-glycosylation site {N283} N-glycosylation site {N344} Glycosyl hydrolase-1 2 {515-953} MOTIF: N-glycosylation site {N607} N-glycosylation site {N612} N-glycosylation site {N694} transmembrane domain {982-1002}

Database Correlations

OMIM correlations MORBIDMAP 604824 UniProt Q9UEF7 Pfam PF00232 Entrez Gene 9365 Kegg hsa:9365 ENZYME 3.2.1.31

References

  1. UniProt :accession Q9UEF7
  2. Bioscience and Technology. May 9, 2014 Gladstone Institutes and UC San Francisco
  3. 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. 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: 26732817
  5. 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: 32282020 https://jamanetwork.com/journals/jamaneurology/fullarticle/2763599