Klotho is an enzyme that in humans is encoded by the KL gene. The three subfamilies of klotho are α-klotho, β-klotho, and γ-klotho. α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21. When the subfamily is not specified, the word "klotho" typically refers to the α-klotho subfamily, because α-klotho was discovered before the other members.
α-klotho is highly expressed in the brain, liver and kidney. β-klotho is predominantly expressed in the liver. γ-klotho is expressed in the skin.
Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form. Proteases can convert the membrane-bound form into the circulating form.
The KL gene encodes a type-I single-pass transmembrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic kidney failure (CKF), and this may be one of the factors underlying degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CKF. Mutations within the family have been associated with ageing, bone loss and alcohol consumption. Transgenic mice that overexpress Klotho live longer than wild-type mice.
Structure
The α-klotho gene is located on chromosome 13, and is translated into a single-pass integral membrane protein. The intracellular portion of the α-klotho protein is short (11 amino acids), whereas the extracellular portion is long (980 amino acids). The transmembrane portion is also comparatively short (21 amino acids). The extracellular portion contains two repeat sequences, termed the KL1 (about 450 amino acids) and KL2 (about 430 amino acids) domains. In the kidney and the choroid plexus of the brain, the transmembrane protein can be proteolytically cleaved to produce a 130-Kilo-Dalton, soluble form of α-klotho protein, released into the circulation and cerebrospinal fluid, respectively. In humans, the secreted form of klotho is more dominant than the membrane form.
The β-Klotho gene is located on chromosome 4. The protein shares homology (43.1% identity and 60.1% similarity) with α-klotho. It should not be confused with the alpha-cut and beta-cut of alpha-klotho, which releases KL1+KL2 and KL2 domain, respectively.
Function
Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Makoto Kuro-o et al. The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology, who spins the thread of human life.
The klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging, and klotho protein has been shown to be a circulating factor detectable in serum that declines with age.
The binding of the endocrine fibroblast growth factors (FGF's, viz., FGF19 and FGF21) to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-klotho. Loss of β-Klotho abolishes all effects of FGF21.
α-klotho, which binds to the endocrine FGF FGF23 changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 (decreasing phosphate reabsorption in the kidney) and decreasing that of TRPC6 (decreasing phosphate absorption from the intestine). α-klotho increases kidney calcium reabsorption by stabilizing TPRV5. About 95% to 98% of Ca2+ filtered from the blood by the kidney is normally reabsorbed by the kidney's renal tubule, which is mediated by TRPV5.
Clinical significance
α-klotho can suppress oxidative stress and inflammation, thereby reducing endothelial dysfunction and atherosclerosis. Blood plasma α-klotho is increased by aerobic exercise, thereby reducing endothelial dysfunction.
β-klotho activation of FGF21 protein has a protective effect on heart muscle cells. Obesity is characterized by FGF21 resistance, believed to be caused by the inhibition of β-klotho by the inflammatory cell signalling protein (cytokine) tumor necrosis factor alpha, but there is evidence against this mechanism.
Klotho is required for oligodendrocyte maturation, myelin integrity, and can protect neurons from toxic effects. Mice deficient in klotho have a reduced number of synapses and cognitive deficits, whereas mice overexpressing klotho have enhanced learning and memory. Research with injections of klotho in primates demonstrates a positive effect on memory that lasts for as long as two weeks.