FIGURE 1.

Klotho structure. The membrane-bound form is single-pass, and consists of two extracellular domains (KL1 and KL2), a transmembrane segment (TM), and a short non-signaling cytoplasmic tail (CYT). The soluble form is generated by proteolytic cleavage, usually by either ADAM10 or ADAM17 enzymes, to release the large soluble form (s-Klotho). This is the major form found in the circulation. It can be further cleaved to generate independent KL1 and KL2 fragments, but these are either minor forms or undetectable in the plasma.