Uncovering secrets behind FTO specificity

3 Jan 2017. NUS scientists have discovered how FTO (or fat mass and obesity-associated protein), a protein strongly associated with obesity and diabetes, opens new treatment options for these metabolic diseases.

FTO is currently of intense biological and medical interest because, to date, this protein provides the strongest link to obesity and diabetes. A team led by Prof Esther WOON from the Department of Pharmacy, NUS has uncovered an ingenious mechanism by which FTO selects its target RNAs (Ribonucleic acid, a molecule essential in various biological roles in coding, decoding, regulation, and expression of genes). They discovered that a widespread chemical modification on messenger RNA called m6A (N⁶-methyladenosine) can crucially influence the shape or conformation of the mRNA strand, thus enabling FTO to recognise its target from amongst a sea of cellular RNAs. This work provides mechanistic insight into how FTO potentially causes obesity and diabetes. It may also pave the way for novel therapeutic strategies against these metabolic diseases.

FTO is found in almost every cell of the body. However, in recent years, it has become increasingly clear that FTO has highly distinct physiological functions that are specifically linked with obesity and diabetes. One intriguing question is how, despite the prevalence of FTO substrates (m6A-modified mRNA) in the cells, only a small fraction of those mRNA strands are actually recognised and acted upon by FTO. Prior to this work, the mechanism behind this incredible selectivity had remained very much a mystery. Uncovering this critical piece of information is essential in expanding our knowledge of FTO’s functions and how it is connected to obesity and diabetes. It is also an important first step in developing safe and effective drug therapies for the growing number of people suffering from these metabolic diseases.

Prof Woon’s team reported for the first time, a unique m6A-based mechanism behind FTO’s specificity. Their results revealed that m6A modification itself can actively remodel the shape or conformation of the mRNA strand, thereby dynamically modulating its interactions with FTO. Through this fascinating mechanism, FTO is able to discriminate its target substrates from other mRNAs, including those with highly similar sequences. This work contributes significantly to our understanding of the underlying (epi)genetic link between FTO and metabolic diseases. Considering that up to 30% of the world’s population may carry the FTO gene variant, results from this work could help tremendously in our battle against obesity.

Work is currently underway to develop a comprehensive map of FTO-regulated mRNAs to identify all possible biological targets of FTO. This will provide greater insights into the significance of FTO to metabolic diseases, and shed light on its potential as a therapeutic target.The wider significance of this work is that it will also unveil a host of other previously unknown disease pathways and therapeutic targets, well beyond the scope of obesity/ diabetes therapeutics.

Figure 1 shows the substrate selectivity and sequence preference of human m6A demethylases FTO and ALKBH5. (a) The extent of demethylation of substrates was determined by HPLC after a 1 hour (FTO) or 30-minute (ALKBH5) incubation at 37 °C, pH 7.4. Steady-state kinetics analyses of the demethylation of consensus (6, 10 and 11) and non-consensus m6A substrates (13) by (b) FTO, and (c) ALKBH5. The Km and kcat values were determined by keeping a constant FTO or ALKBH5 concentration of 0.5 μ M. Errors represent standard deviation of three replicates.

Reference

Zou S; Toh JDW; Wong KHQ; Gao YG; Hong WJ; Woon ECY*, “N⁶-Methyladenosine: a conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5″, SCIENTIFIC REPORTS Volume: 6 Article Number: 25677 DOI: 10.1038/srep25677 Published: 2016