α-Klotho (3.5pg)

Klotho, encoded by the KL gene, exists in three subfamilies: α-klotho, β-klotho, and γ-klotho. α-klotho activates FGF23, while β-klotho triggers FGF19 and FGF21. Typically, when the specific subfamily isn’t specified, “klotho” refers to α-klotho, which was discovered before the other subfamilies.

α-klotho is prominently expressed in the brain, liver, and kidney, while β-klotho predominantly shows up in the liver, and γ-klotho is found in the skin.

Klotho can take on a membrane-bound or soluble circulating form, with proteases facilitating the conversion from the former to the latter.

The KL gene encodes a type-I single-pass transmembrane protein related to β-glucuronidases. Reduced production of this protein in chronic kidney failure patients might contribute to degenerative processes like arteriosclerosis, osteoporosis, and skin atrophy. Mutations within the gene family have been linked to aging, bone loss, and alcohol consumption. Transgenic mice overexpressing Klotho tend to live longer than their wild-type counterparts.

The α-klotho gene, situated on chromosome 13, translates into a single-pass integral membrane protein. Its intracellular section is brief (11 amino acids), while the extracellular part is extensive (980 amino acids). The transmembrane part is relatively short (21 amino acids). The extracellular segment comprises two repeat sequences, KL1 (around 450 amino acids) and KL2 (approximately 430 amino acids). In specific tissues like the kidney and choroid plexus of the brain, the transmembrane protein can be cleaved to produce a soluble form of α-klotho protein, released into the circulation and cerebrospinal fluid, respectively. In humans, the secreted form of klotho is more prevalent than the membrane-bound version.