Browsing by Subject "irisin"
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Item Open Access Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor?(Adipocyte, 2013-10-01) Erickson, Harold PFNDC5 (fibronectin domain-containing [protein] 5) was initially discovered and characterized by two groups in 2002. In 2011 FNDC5 burst into prominence as the parent of irisin, a small protein containing the fibronectin type III domain. Irisin was proposed to be secreted by skeletal muscle cells in response to exercise, and to circulate to fat tissue where it induced a transition to brown fat. Since brown fat results in dissipation of energy, this pathway is of considerable interest for metabolism and obesity. Here I review the original discoveries of FNDC5 and the more recent discovery of irisin. I note in particular three problems in the characterization of irisin: the antibodies used to detect irisin in plasma lack validity; the recombinant protein used to demonstrate activity in cell culture was severely truncated; and the degree of shedding of soluble irisin from the cell surface has not been quantitated. The original discovery proposing that FNDC5 may be a transmembrane receptor may deserve a new look.Item Open Access Progress and challenges in the biology of FNDC5 and irisin.(Endocrine reviews, 2021-01-25) Maak, Steffen; Norheim, Frode; Drevon, Christian A; Erickson, Harold PIn 2002, a transmembrane protein now known as FNDC5 was discovered and shown to be expressed in skeletal muscle, heart and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved,traveled to white adipose tissue and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1,000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions are questioned for use of flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin to bone remodeling and to brain, with effects potentially related to Alzheimer's disease. We also discuss some discrepancies between research groups and mechanisms that need to be determined. Some important questions raised in the initial discovery of irisin like the role of the mutant start codon of human FNDC5, the mechanism of ectodomain cleavage remain to be answered. Apart from these specific questions, a promising new tool has been developed - mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.Item Open Access Spontaneous Unfolding-Refolding of Fibronectin Type III Domains Assayed by Thiol Exchange: THERMODYNAMIC STABILITY CORRELATES WITH RATES OF UNFOLDING RATHER THAN FOLDING.(J Biol Chem, 2017-01-20) Shah, Riddhi; Ohashi, Tomoo; Erickson, Harold P; Oas, Terrence GGlobular proteins are not permanently folded but spontaneously unfold and refold on time scales that can span orders of magnitude for different proteins. A longstanding debate in the protein-folding field is whether unfolding rates or folding rates correlate to the stability of a protein. In the present study, we have determined the unfolding and folding kinetics of 10 FNIII domains. FNIII domains are one of the most common protein folds and are present in 2% of animal proteins. FNIII domains are ideal for this study because they have an identical seven-strand β-sandwich structure, but they vary widely in sequence and thermodynamic stability. We assayed thermodynamic stability of each domain by equilibrium denaturation in urea. We then assayed the kinetics of domain opening and closing by a technique known as thiol exchange. For this we introduced a buried Cys at the identical location in each FNIII domain and measured the kinetics of labeling with DTNB over a range of urea concentrations. A global fit of the kinetics data gave the kinetics of spontaneous unfolding and refolding in zero urea. We found that the folding rates were relatively similar, ∼0.1-1 s(-1), for the different domains. The unfolding rates varied widely and correlated with thermodynamic stability. Our study is the first to address this question using a set of domains that are structurally homologous but evolved with widely varying sequence identity and thermodynamic stability. These data add new evidence that thermodynamic stability correlates primarily with unfolding rate rather than folding rate. The study also has implications for the question of whether opening of FNIII domains contributes to the stretching of fibronectin matrix fibrils.