Expression of FNDC5 (fibronectin type III domain containing 5), also known as FRCP2 and PeP, is stimulated in muscle by PGC1-α in response to exercise. It is a signal peptide with two fibronectin domains in its amino (N)-terminal part and a hydrophobic domain inserted in the lipidic bilayer at carboxy (C)-terminal domain. The first 29 aa of the mouse FNDC5 are a signal peptide, followed immediately by the single FNIII domain of 94 aa. The next 28 aa are of unknown structure and function and contain the putative cleavage site for irisin. This is followed by a 19 aa transmembrane domain and a 39 aa cytoplasmic domain. FNDC5 is thus a type I transmembrane protein with its FNIII domain extracellular, similar to some cytokine receptors. This structure is synthesized as a type I membrane protein and followed by proteolytic cleavage realising amino (N)-terminal part of the protein into the extracellular to circulation.
