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The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation.

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Date
2013-11
Authors
Schumacher, Maria A
Chinnam, Nagababu
Ohashi, Tomoo
Shah, Riddhi Sanjay
Erickson, Harold P
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Abstract
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.
Type
Journal article
Subject
Humans
Fibronectins
Recombinant Proteins
Crystallography, X-Ray
Protein Structure, Quaternary
Protein Structure, Secondary
Protein Structure, Tertiary
Structure-Activity Relationship
Glycosylation
Protein Multimerization
Permalink
https://hdl.handle.net/10161/16452
Published Version (Please cite this version)
10.1074/jbc.m113.516641
Publication Info
Schumacher, Maria A; Chinnam, Nagababu; Ohashi, Tomoo; Shah, Riddhi Sanjay; & Erickson, Harold P (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.
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Scholars@Duke

Erickson

Harold Paul Erickson

James B. Duke Distinguished 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

Tomoo Ohashi

Assistant Research Professor of Cell Biology
Schumacher

Maria Anne Schumacher

Nanaline H. Duke Distinguished Professor of Biochemistry
Alphabetical list of authors with Scholars@Duke profiles.
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