The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation.
Repository Usage Stats
Irisin was recently identified as a putative myokine that is induced by exercise. Studies suggest that it is produced by cleavage of the FNDC5 (fibronectin domain-containing protein 5) receptor; irisin corresponds to the extracellular receptor ectodomain. Data suggesting that irisin stimulates white-to-brown fat conversion have led to the hypothesis that it does so by binding an unknown receptor, thus functioning as a myokine. As brown fat promotes energy dissipation, myokines that elicit the transformation of white to brown fat have potentially profound benefits in the treatment of obesity and metabolic disorders. Understanding the molecular basis for such exercise-induced phenomena is thus of considerable interest. Moreover, FNDC5-like receptors are highly conserved and have been shown to be critical for neuronal development. However, the structural and molecular mechanisms utilized by these proteins are currently unknown. Here, we describe the crystal structure and biochemical characterization of the FNDC5 ectodomain, corresponding to the irisin myokine. The 2.28 Å structure shows that irisin consists of an N-terminal fibronectin III (FNIII)-like domain attached to a flexible C-terminal tail. Strikingly, the FNIII-like domain forms a continuous intersubunit β-sheet dimer, previously unobserved for any FNIII protein. Biochemical data confirm that irisin is a dimer and that dimerization is unaffected by glycosylation. This finding suggests a possible mechanism for receptor activation by the irisin domain as a preformed myokine dimer ligand or as a paracrine or autocrine dimerization module on FNDC5-like receptors.
Protein Structure, Quaternary
Protein Structure, Secondary
Protein Structure, Tertiary
Published Version (Please cite this version)10.1074/jbc.m113.516641
Publication InfoChinnam, Nagababu; Erickson, Harold Paul; Ohashi, Tomoo; Schumacher, Maria; & Shah, Riddhi Sanjay (2013). The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation. The Journal of biological chemistry, 288(47). 10.1074/jbc.m113.516641. Retrieved from https://hdl.handle.net/10161/16452.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
More InfoShow full item record
James B. Duke Professor of Cell Biology
Cytoskeleton: It is now clear that the actin and microtubule cytoskeleton originated in bacteria. Our major research is on FtsZ, the bacterial tubulin homolog, which assembles into a contractile ring that divides the bacterium. We have studied FtsZ assembly in vitro, and found that it assembles into thin protofilaments (pfs). Dozens of these pfs are further clustered to form the contractile Z-ring in vivo. Some important discoveries in the last ten years include: &bul
Assistant Research Professor of Cell Biology
Nanaline H. Duke Professor of Biochemistry
Alphabetical list of authors with Scholars@Duke profiles.
Showing items related by title, author, creator, and subject.
The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase. Caron, MG; Inglese, J; Lefkowitz, Robert J; Lorenz, W; Onorato, JJ; Palczewski, K (Proc Natl Acad Sci U S A, 1991-10-01)Light-dependent deactivation of rhodopsin as well as homologous desensitization of beta-adrenergic receptors involves receptor phosphorylation that is mediated by the highly specific protein kinases rhodopsin kinase (RK) ...
Headd, Jeffrey John (2009)As of late 2009, the Protein Data Bank (PDB) has grown to contain over 70,000 models. This recent increase in the amount of structural data allows for more extensive explication of the governing principles of macromolecular ...
Arthos, J; Bewley, CA; Bonsignori, Mattia; Boyington, JC; Burton, DR; Carrico, C; Chuang, G-Y; ... (47 authors) (Nature, 2011-11-23)Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity ...