FNDC5

Fibronectin type III domain containing 5
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4LSD
Identifiers
Symbols	FNDC5 ; FRCP2; irisin
External IDs	OMIM: 611906 HomoloGene: 17812 GeneCards: FNDC5 Gene
Gene ontology Molecular function • molecular_function • hormone activity Cellular component • extracellular region • peroxisomal membrane • endoplasmic reticulum • plasma membrane • integral component of membrane Biological process • biological_process • response to muscle activity • positive regulation of brown fat cell differentiation Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	252995	384061
Ensembl	ENSG00000160097	ENSMUSG00000001334
UniProt	Q8NAU1	Q8K4Z2
RefSeq (mRNA)	NM_001171940	NM_027402
RefSeq (protein)	NP_001165411	NP_081678
Location (UCSC)	Chr 1: 32.86 – 32.87 Mb	Chr 4: 129.14 – 129.14 Mb
PubMed search	[1]	[2]

Fibronectin type III domain-containing protein 5, the precursor of irisin, is a protein that is encoded by the FNDC5 gene.

Fibronectin domain-containing protein 5 is a membrane protein comprising a short cytoplasmic domain, a transmembrane segment, and an ectodomain consisting of a ~100 kDa fibronectin type III (FNIII) domain. The ectodomain has been proposed to be cleaved to give a soluble peptide hormone named irisin. It has been proposed that irisin is secreted from muscle in response to exercise, and may mediate some beneficial effects of exercise in humans and the potential for generating weight loss and blocking diabetes has been suggested. while others have questioned these findings.

Discovery

FNDC5 was initially discovered during a genome search for fibronectin type III domains and also independently in a search for peroxisomal proteins. Irisin was found to be a cleaved version of FNDC5. The cleaved product has been called irisin, after the Greek messenger goddess Iris.

Biosynthesis and secretion

The FNDC5 gene encodes a prohormone, a single-pass type I membrane protein (human, 212 amino acids; mouse and rat, 209 amino acids) that is upregulated by muscular exercise and undergoes post-translational processing to generate irisin. The sequence of the protein includes a signal peptide, a single fibronectin type III domain, and a C-terminal hydrophobic domain that is anchored in the cell membrane. The production of irisin is similar to the shedding and release of other hormones and hormone-like polypeptides, such as epidermal growth factor and TGF alpha, from transmembrane precursors. After the N-terminal signal peptide is removed, the peptide is proteolytically cleaved from the C-terminal moiety, glycosylated, and released as a hormone of 112 amino acids (in human, amino acids 32-143 of the full-length protein; in mouse and rat, amino acids 29-140) that comprises most of the FNIII repeat region. The sequence of irisin, the cleaved and secreted portion of FNDC5, is highly conserved in mammals; the human and murine sequences are identical. However, the start codon of human FNDC5 is mutated to ATA, which causes it to be expressed at only 1% the level of other animals with the normal ATG start - though its circulation levels are still on par with other key humanhormones, such as insulin.

A difference in the nucleotide sequence of human FNDC5 from that of mouse Fndc5 creates a different initiation codon, potentially generating a protein that begins at methionine-76 (Met-76). A protein initiated at Met-76 would be missing the signal peptide and would be trapped in the cytoplasm. Via mass spectrometry, irisin has been found to circulate in humans in levels similar to other key hormones, such as insulin.

Function

Exercise causes increased expression in muscle of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha), which is involved in adaptation to exercise. In mice, this causes production of the FNDC5 protein which is cleaved to give a new product irisin. Due to its production through a mechanism initiated by muscular contraction, irisin has been classified as a myokine.

Based on the findings that FNDC5 induces thermogenin expression in fat cells, overexpression of FNDC5 in the liver of mice prevents diet-induced weight gain, and FNDC5 mRNA levels are elevated in human muscle samples after exercise, it has been proposed that irisin promotes the conversion of white fat to brown fat in humans which would make it a health promoting hormone. However this proposal has been challenged since FNDC5 is upregulated only in highly active elderly humans.

In mice, irisin released from skeletal muscle during exercise also acts directly on bone by increasing cortical bone mineral density, bone perimeter and polar moment of inertia.

See also

• GW 501516