The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation.
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 articleSubject
HumansFibronectins
Recombinant Proteins
Crystallography, X-Ray
Protein Structure, Quaternary
Protein Structure, Secondary
Protein Structure, Tertiary
Structure-Activity Relationship
Glycosylation
Protein Multimerization
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https://hdl.handle.net/10161/16452Published Version (Please cite this version)
10.1074/jbc.m113.516641Publication 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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Show full item recordScholars@Duke
Harold Paul Erickson
James B. Duke Distinguished Professor Emeritus
Recent research has been on cytoskeleton (eukaryotes and bacteria); a skirmish to
debunk the irisin story; a reinterpretation of proposed multivalent binders of the
coronavirus spike protein. I have also published an ebook on "Principles of Protein-Protein
Association" suitable for a course module or individual learning.
Tomoo Ohashi
Assistant Research Professor of Cell Biology
Maria Anne Schumacher
Nanaline H. Duke Distinguished Professor of Biochemistry
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