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1  structure 51  species 0  interactions 102  sequences 3  architectures

Family: FTO_NTD (PF12933)

Summary: FTO catalytic domain

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This is the Wikipedia entry entitled "FTO gene". More...

FTO gene Edit Wikipedia article

Fat mass and obesity associated
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols FTO; KIAA1752; MGC5149
External IDs OMIM610966 MGI1347093 HomoloGene8053 GeneCards: FTO Gene
EC number 1.14.11.-
RNA expression pattern
PBB GE FTO 209702 at tn.png
PBB GE FTO gnf1h06407 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 79068 26383
Ensembl ENSG00000140718 ENSMUSG00000055932
UniProt Q9C0B1 Q8BGW1
RefSeq (mRNA) NM_001080432 NM_011936
RefSeq (protein) NP_001073901 NP_036066
Location (UCSC) Chr 16:
53.74 – 54.16 Mb
Chr 8:
91.31 – 91.67 Mb
PubMed search [1] [2]

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified.[1] Certain variants of the FTO gene appear to be correlated with obesity in humans.[2][3]

Function[edit]

The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA.[3][4] Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency.[3] The nucleoside N6-methyladenosine, an abundant modification in RNA, was then found to be a major substrate of FTO.[1][5] The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexogenic galanin like peptide which is involved in the stimulation of food intake.[6]

Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.[7]

FTO demethylates m6A in mRNA[edit]

N6-methyladenosine (m6A) is an abundant modification in mRNA and is found within some viruses,[8][9] and most eukaryotes including mammals,[10][11][12][13] insects,[14] plants,[15][16][17]and yeast.[18][19] It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.[20][21] Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit.[22] In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU[23] and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA[24] and in bovine prolactin mRNA.[25] In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail.[26]

Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of [G/A/U][G>A]m6AC[U>A/C]<[20][21] consistent with the previously identified motif.[23] Sites preferentially appear in two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and mouse.[20][21] A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis.

FTO demethylates m6A containing RNA efficiently in vitro.[1] FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells.[20] FTO partially co-localizes with nuclear speckles, which supports the notion that m6A in nuclear RNA is a major physiological substrate of FTO. Function of FTO likely affects the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of m6A in nuclear RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA.[1][20]

Tissue distribution[edit]

The FTO gene is widely expressed in both fetal and adult tissues.[2]

Clinical significance[edit]

Association with obesity[edit]

A study of 38,759 Europeans for variants of FTO identified an obesity risk allele.[2] In particular, carriers of one copy of the allele weighed on average 1.2 kilograms (2.6 lb) more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 kilograms (6.6 lb) more and had a 1.67-fold higher rate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is not directly associated with diabetes however increased body-fat also increases the risk of developing Type 2 Diabetes.[27]

Simultaneously, a study in 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association of SNPs in the very same region of FTO (rs14210850) [28] The authors found that this variation, or a variation in strong LD with this variation explains 1% of the population BMI variance and 22% of the population attributable risk of obesity. The authors of this study claim that while obesity was already known to have a genetic component (from twin studies), no replicated previous study has ever identified an obesity risk allele that was so common in the human population. The risk allele is a cluster of 10 single nucleotide polymorphism in the first intron of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese. Furthermore morbid obesity is associated with a combination of FTO and INSIG2 single nucleotide polymorphisms.[29]

In 2009 variants in the FTO gene were further confirmed to associate with obesity in two very large genome wide association studies of body mass index (BMI).[30][31]

In adult humans it was shown that adults bearing the at risk AT and AA alleles at rs9939609 consumed between 500 and 1250 kJ more each day than those carrying the protective TT genotype (equivalent to between 125 and 280 kcal per day more intake).[32] The same study showed that there was no impact of the polymorphism on energy expenditure. This finding of an effect of the rs9939609 polymorphism on food intake or satiety has been independently replicated in five subsequent studies (in order of publication).[33][34][35][36][37] Three of these subsequent studies also measured resting energy expenditure and confirmed the original finding that there is no impact of the polymorphic variation at the rs9939609 locus on energy expenditure. A different study explored the effects of variation in two different SNPs in the FTO gene (rs17817449 and rs1421085) and suggested there might be an effect on circulating leptin levels and energy expenditure, but this latter effect disappeared when the expenditure was normalised for differences in body composition.[38] The accumulated data across seven independent studies therefore clearly implicates the FTO gene in humans as having a direct impact on food intake but no effect on energy expenditure.

Association with Alzheimer's disease[edit]

Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain[39] and an impaired verbal fluency performance.[40] Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.[41]

Association with other diseases[edit]

The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower HDL cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in body mass index.[42]

Model organisms[edit]

Model organisms have been used in the study of FTO function. In contrast to the findings in humans deletion, analysis of the Fto gene in mice showed loss of function is associated with no differences in energy intake but greater energy expenditure and this results in a reduction of body weight and fatness.[43]

Another conditional knockout mouse line, called Ftotm1a(EUCOMM)Wtsi[49][50] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[51][52][53] Male and female animals from this line underwent a standardized phenotypic screen to determine the effects of deletion.[47][54] Twenty five tests were carried out on mutant mice and only significant skeletal abnormalities were observed, including kyphosis and abnormal vertebral transverse processes, and only in female homozygous mutant animals. [47]

The reasons for the differences in FTO phenotype between humans and different lines of mice is presently uncertain. However, many other genes involved in regulation of energy balance exert effects on both intake and expenditure.

Origin of name[edit]

The gene's abbreviation is FTO because it is one of 6 genes that lie in a deleted region in mice that results in a fused toes (FT) phenotype and other abnormalities.[55][56]

References[edit]

  1. ^ a b c d Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C (December 2011). "N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO". Nat. Chem. Biol. 7 (12): 885–7. doi:10.1038/nchembio.687 . PMC 3218240. PMID 22002720. 
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  27. ^ http://www.nature.com/nutd/journal/v2/n7/fig_tab/nutd20129t1.html#figure-title
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  30. ^ Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I, Jonsdottir T, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Jonsson F, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Lauritzen T, Aben KK, Verbeek AL, Roeleveld N, Kampman E, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Becker DM, Gulcher J, Kiemeney LA, Pedersen O, Kong A, Thorsteinsdottir U, Stefansson K (January 2009). "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity". Nat. Genet. 41 (1): 18–24. doi:10.1038/ng.274 . PMID 19079260. 
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  32. ^ Speakman JR, Rance KA, Johnstone AM (August 2008). "Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure". Obesity (Silver Spring) 16 (8): 1961–5. doi:10.1038/oby.2008.318 . PMID 18551109. 
  33. ^ Wardle J, Carnell S, Haworth CM, Farooqi IS, O'Rahilly S, Plomin R (September 2008). "Obesity associated genetic variation in FTO is associated with diminished satiety". J. Clin. Endocrinol. Metab. 93 (9): 3640–3. doi:10.1210/jc.2008-0472 . PMID 18583465. 
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  37. ^ Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN (December 2008). "An obesity-associated FTO gene variant and increased energy intake in children". N. Engl. J. Med. 359 (24): 2558–66. doi:10.1056/NEJMoa0803839 . PMID 19073975. 
  38. ^ Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, Engert JC (April 2008). "Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study". Diabetes 57 (4): 1147–50. doi:10.2337/db07-1267 . PMID 18316358. 
  39. ^ Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR, Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM (May 2010). "A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly". Proc. Natl. Acad. Sci. U.S.A. 107 (18): 8404–9. Bibcode:2010PNAS..107.8404H. doi:10.1073/pnas.0910878107 . PMC 2889537. PMID 20404173. 
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External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

FTO catalytic domain Provide feedback

This domain is the catalytic AlkB-like domain from the FTO protein [1]. This domain catalyses a demethylase activity with a preference for 3-methylthymidine.

Literature references

  1. Han Z, Niu T, Chang J, Lei X, Zhao M, Wang Q, Cheng W, Wang J, Feng Y, Chai J;, Nature. 2010; [Epub ahead of print]: Crystal structure of the FTO protein reveals basis for its substrate specificity. PUBMED:20376003 EPMC:20376003


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR024367

Alpha-ketoglutarate-dependent dioxygenase FTO, also known as Fat mass and obesity-associated protein, is a nucleus protein which belongs to the FTO family. This enzyme is a dioxygenase that repairs alkylated DNA and RNA by oxidative demethylation [PUBMED:17991826]. FTO activity is highest towards single-stranded RNA containing 3-methyluracil, followed by single-stranded DNA containing 3-methylthymine. FTO has low demethylase activity towards single-stranded DNA containing 1-methyladenine or 3-methylcytosine [PUBMED:18775698]. FTO has no activity towards 1-methylguanine. It has no detectable activity towards double-stranded DNA. FTO requires molecular oxygen, alpha-ketoglutarate and iron. FTO contributes to the regulation of the global metabolic rate, energy expenditure and energy homeostasis. It contributes to the regulation of body size and body fat accumulation as well [PUBMED:19234441].

This domain is the catalytic AlkB-like domain from the FTO protein [PUBMED:20376003]. This domain catalyses a demethylase activity with a preference for 3-methylthymidine.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cupin (CL0029), which has the following description:

This clan represents the conserved barrel domain of the 'cupin' superfamily [1] ('cupa' is the Latin term for a small barrel). The cupin fold is found in a wide variety of enzymes, but notably contains the non-enzymatic seed storage proteins also.

The clan contains the following 53 members:

2OG-Fe_Oxy_2 2OG-FeII_Oxy 2OG-FeII_Oxy_2 2OG-FeII_Oxy_3 2OG-FeII_Oxy_4 2OG-FeII_Oxy_5 3-HAO AraC_binding AraC_binding_2 AraC_N ARD Asp_Arg_Hydrox Auxin_BP CDO_I CENP-C_C CsiD Cupin_1 Cupin_2 Cupin_3 Cupin_4 Cupin_5 Cupin_6 Cupin_7 Cupin_8 dTDP_sugar_isom DUF1255 DUF1479 DUF1498 DUF1637 DUF1971 DUF386 DUF4437 Ectoine_synth EutQ FdtA FTO_NTD GPI HgmA HutD JmjC KduI MannoseP_isomer Ofd1_CTDD Oxygenase-NA PhyH Pirin Pirin_C PMI_typeI Pox_C4_C10 TauD Tet_JBP VIT VIT_2

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

  Seed
(8)
Full
(102)
Representative proteomes NCBI
(84)
Meta
(3)
RP15
(8)
RP35
(11)
RP55
(20)
RP75
(40)
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(8)
Full
(102)
Representative proteomes NCBI
(84)
Meta
(3)
RP15
(8)
RP35
(11)
RP55
(20)
RP75
(40)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(8)
Full
(102)
Representative proteomes NCBI
(84)
Meta
(3)
RP15
(8)
RP35
(11)
RP55
(20)
RP75
(40)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Jackhmmer:Q9C0B1
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 8
Number in full: 102
Average length of the domain: 255.40 aa
Average identity of full alignment: 57 %
Average coverage of the sequence by the domain: 61.02 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 10.0
Trusted cut-off 27.2 15.8
Noise cut-off 26.0 9.9
Model length: 253
Family (HMM) version: 2
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the FTO_NTD domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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