Fibronectin type III domain-containing protein 5 (FNDC5) (FNDC5)

Fibronectin type III domain-containing protein 5 (FNDC5) is a highly conserved, type I transmembrane protein expressed mainly in skeletal muscle but also in other tissues. Its N-terminal fibronectin type III (FNIII) domain is proteolytically cleaved to release a small, secreted hormone called irisin, which is exercise-inducible and has been implicated in the regulation of energy metabolism and fat browning[1][3]. The structure of irisin is unique among FNIII proteins, forming a tight, continuous inter-subunit β-sheet dimer—a feature not observed in other FNIII domains[2]. Irisin may function as a myokine, mediating cross-talk between muscle and other tissues, particularly adipose tissue, and is hypothesized to play a role in obesity and metabolic disease, though its significance in human physiology is debated due to weak FNDC5 gene expression in humans[3]. The receptor for irisin is currently unidentified, and the signaling mechanisms remain speculative. Notably, human FNDC5 mRNA translation is inefficient due to a non-canonical start codon, potentially limiting the physiological impact of this pathway in humans[3].

Other names

IrisinFibronectin type III repeat-containing protein 2 (FRCP2)FNDC5 proteinFNDC5 receptorfibronectin domain-containing protein 5fibronectin type III repeat-containing protein 2

Irisin, the cleaved extracellular domain of FNDC5, acts as an autocrine, paracrine, or endocrine signaling molecule. The FNDC5 protein is integrated into the cell membrane; proteolytic cleavage releases irisin, which circulates and likely binds an as-yet unidentified receptor. The FNDC5/irisin system may stimulate the “browning” of white fat, increasing energy expenditure via thermogenesis. The unique dimeric structure of irisin suggests novel receptor-activation mechanisms, distinct from typical receptor dimerization[1][2]. FNDC5/irisin may also have cell-cell adhesion functions[2].