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Resistin Edit Wikipedia article
|Symbols||; ADSF; FIZZ3; RETN1; RSTN; XCP1|
|RNA expression pattern|
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich adipose-derived peptide hormone that in humans is encoded by the RETN gene.
In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue. The length of the resistin pre-peptide in human is 108 amino acid residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa. Resistin is an adipose-derived hormone (similar to a cytokine) whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes mellitus (T2DM).
Resistin has been shown to cause "high levels of 'bad' cholesterol (low-density lipoprotein or LDL), increasing the risk of heart disease [...] resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in arteries, increasing the risk of heart disease. [...] resistin adversely impacts the effects of statins, the main cholesterol-reducing drug used in the treatment and prevention of cardiovascular disease."
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine. It was called "resistin" because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, rats, and mice). Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.
This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects.
Inflammation is the first innate immune response to infection or irritation resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine, prostaglandin, and pro-inflammatory cytokines. As cited, it has recently been found that resistin also participates in the inflammatory response.
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion. It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide, which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation, which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with lowered renal function and inflammation, but not with insulin resistance. Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
Obesity and insulin resistance
Much of what is hypothesized about a resistin role in energy metabolism and T2DM can be derived from studies showing strong correlations between resistin and obesity. The underlying belief among those in support of this theory is that serum resistin levels will increase with increased adiposity. Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment. Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin. This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance that appears to be associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance. This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM. If resistin does contribute to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects might deliver immense therapeutic benefits.
The amount of evidence supporting the resistin link theory between obesity and T2DM is vast. Nevertheless, this theory lacks support from the entire scientific community, as the number of studies presenting evidence against it continues to expand. Such studies have found significantly decreased serum concentrations of resistin with increased adiposity, suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between obesity and T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented; such studies instead report that weight loss is associated with marked increases in serum resistin. The idea that resistin links obesity to T2DM is now under even more scrutiny, as recent investigations have confirmed ubiquitous expression of resistin in many tissues, rather than those only characteristic of obesity, such as adipocytes.
Although nearly as many scientists oppose the theory as those who support it, there is sufficient evidence to support the idea that resistin does have some incompletely defined role in energy homeostasis, while also demonstrating properties that help to incite inflammatory responses to sites of infection.
Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions that make up its structure. The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. Each protein subunit comprises a carboxy-terminal disulfide-rich beta sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. The globular domain from resistin contains five disulfide bonds (Cys35-Cys88, Cys47-Cys87, Cys56-Cys73, Cys58-Cys75, and Cys62-Cys77). This suggests that the disulfide pattern will be conserved.
The interchain disulfide bonds of resistin and resistin-like molecule β (RELMß) are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds is 9.9%, and 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin’s disulfides in high-resolution.
A Cys6Ser resistin mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect a mandatory step toward activation. Other results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.
- doi:10.1126/science.1093466. PMID 15155948.; Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L (May 2004). "Disulfide-dependent multimeric assembly of resistin family hormones". Science 304 (5674): 1154–8.
- Wang H, Chu WS, Hemphill C, Elbein SC (June 2002). "Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians". J. Clin. Endocrinol. Metab. 87 (6): 2520–4. doi:10.1210/jc.87.6.2520. PMID 12050208.
- Lazar MA (October 2007). "Resistin- and Obesity-associated metabolic diseases". Horm. Metab. Res. 39 (10): 710–6. doi:10.1055/s-2007-985897. PMID 17952831.
- "Canadian scientists discover cause of high cholesterol".
- Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA (January 2001). "The hormone resistin links obesity to diabetes". Nature 409 (6818): 307–12. doi:10.1038/35053000. PMID 11201732.
- Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV (November 2003). "Serum resistin (FIZZ3) protein is increased in obese humans". J. Clin. Endocrinol. Metab. 88 (11): 5452–5. doi:10.1210/jc.2002-021808. PMID 14602788.
- Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N (October 2002). "Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?". Diabetes 51 (10): 2951–8. doi:10.2337/diabetes.51.10.2951. PMID 12351432.
- Levy JR, Davenport B, Clore JN, Stevens W (March 2002). "Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats". Am. J. Physiol. Endocrinol. Metab. 282 (3): E626–33. doi:10.1152/ajpendo.00346.2001. PMID 11832366.
- McTernan, CL; McTernan, PG; Harte, AL; Levick, PL; Barnett, AH; Kumar, S (2002). "Resistin, central obesity, and type 2 diabetes". The Lancet 359 (9300): 46–47. doi:10.1016/S0140-6736(02)07281-1. ISSN 0140-6736.
- Adeghate E (October 2004). "An update on the biology and physiology of resistin". Cell. Mol. Life Sci. 61 (19–20): 2485–96. doi:10.1007/s00018-004-4083-2. PMID 15526156.
- Stumvoll M, Häring H (November 2002). "Resistin and adiponectin--of mice and men". Obes. Res. 10 (11): 1197–9. doi:10.1038/oby.2002.162. PMID 12429885.
- Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, Simón I, Soler J, Richart C (June 2004). "Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity". Obes. Res. 12 (6): 962–71. doi:10.1038/oby.2004.118. PMID 15229336.
- Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale FV Jr, Shelton DL, Hébert CC (August 2000). "FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family". EMBO J. 19 (15): 4046–55. doi:10.1093/emboj/19.15.4046. PMC 306596. PMID 10921885.
- Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG (January 2007). "The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes". J. Clin. Endocrinol. Metab. 92 (1): 270–6. doi:10.1210/jc.2006-1151. PMID 17062773.
- Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M (December 2006). "Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients". Transplant. Proc. 38 (10): 3434–6. doi:10.1016/j.transproceed.2006.10.140. PMID 17175295.
- Nagaev I, Bokarewa M, Tarkowski A, Smith U (2006). Valcarcel, Juan, ed. "Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes". PLoS ONE 1 (1): e31. doi:10.1371/journal.pone.0000031. PMC 1762367. PMID 17183659.
- Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R (November 2002). "Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss". Obes. Res. 10 (11): 1095–103. doi:10.1038/oby.2002.149. PMID 12429872.
- Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ (September 2005). "Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway". Biochem. Biophys. Res. Commun. 334 (4): 1092–101. doi:10.1016/j.bbrc.2005.06.202. PMID 16039994.
- Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA (August 2003). "Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction". Circulation 108 (6): 736–40. doi:10.1161/01.CIR.0000084503.91330.49. PMID 12874180.
- Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL (October 2002). "Lipopolysaccharide increases resistin gene expression in vivo and in vitro". FEBS Lett. 530 (1–3): 158–62. doi:10.1016/S0014-5793(02)03450-6. PMID 12387885.
- Wellen KE, Hotamisligil GS (May 2005). "Inflammation, stress, and diabetes". J. Clin. Invest. 115 (5): 1111–9. doi:10.1172/JCI25102. PMC 1087185. PMID 15864338.
- Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME (April 2004). "Adiponectin differentially regulates cytokines in porcine macrophages". Biochem. Biophys. Res. Commun. 316 (3): 924–9. doi:10.1016/j.bbrc.2004.02.130. PMID 15033490.
- Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y (September 2000). "Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages". Blood 96 (5): 1723–32. PMID 10961870.
- Axelsson J, Bergsten A, Qureshi AR, Heimbürger O, Bárány P, Lönnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P (February 2006). "Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance". Kidney Int. 69 (3): 596–604. doi:10.1038/sj.ki.5000089. PMID 16395259.
- Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P (May 2004). "Changes in glycemia by leptin administration or high-fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis". Endocrinology 145 (5): 2206–13. doi:10.1210/en.2003-1679. PMID 14962997.
- Lee JH, Bullen JW, Stoyneva VL, Mantzoros CS (March 2005). "Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia". Am. J. Physiol. Endocrinol. Metab. 288 (3): E625–32. doi:10.1152/ajpendo.00184.2004. PMID 15522996.
- Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S (April 2004). "Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines". Metab. Clin. Exp. 53 (4): 430–4. doi:10.1016/j.metabol.2003.11.022. PMID 15045687.
- McTernan, P. G. (2002). "Increased Resistin Gene and Protein Expression in Human Abdominal Adipose Tissue". Journal of Clinical Endocrinology & Metabolism 87 (5): 2407–2407. doi:10.1210/jcem.87.5.8627. ISSN 0021-972X.
- Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS (August 2003). "The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity". Diabetes Nutr. Metab. 16 (4): 243–50. PMID 14768774.
- Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (November 2002). "A central role for JNK in obesity and insulin resistance". Nature 420 (6913): 333–6. doi:10.1038/nature01137. PMID 12447443.
- Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS (July 2004). "Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting". Diabetes 53 (7): 1671–9. doi:10.2337/diabetes.53.7.1671. PMID 15220189.
- Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ (October 2003). "Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance". Eur. J. Endocrinol. 149 (4): 331–5. doi:10.1530/eje.0.1490331. PMID 14514348.
- Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G (July 2003). "A promoter genotype and oxidative stress potentially link resistin to human insulin resistance". Diabetes 52 (7): 1611–8. doi:10.2337/diabetes.52.7.1611. PMID 12829623.
- Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M (January 2004). "Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes". Clin. Chim. Acta 339 (1–2): 57–63. doi:10.1016/j.cccn.2003.09.009. PMID 14687894.
- McTernan PG, Fisher FM, Valsamakis G, et al. (December 2003). "Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes". J. Clin. Endocrinol. Metab. 88 (12): 6098–106. doi:10.1210/jc.2003-030898. PMID 14671216.
- Tjokroprawiro A (2006). "New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer)". Acta Med Indones 38 (3): 160–6. PMID 17119268.
- Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M (January 2003). "Resistin release by human adipose tissue explants in primary culture". Biochem. Biophys. Res. Commun. 300 (3): 674–8. doi:10.1016/S0006-291X(02)02864-4. PMID 12507502.
- Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS (October 2003). "Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects". J. Clin. Endocrinol. Metab. 88 (10): 4848–56. doi:10.1210/jc.2003-030519. PMID 14557464.
- Nagaev I, Smith U (July 2001). "Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle". Biochem. Biophys. Res. Commun. 285 (2): 561–4. doi:10.1006/bbrc.2001.5173. PMID 11444881.
- Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR' (April 2004). "Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects". J. Clin. Endocrinol. Metab. 89 (4): 1844–8. doi:10.1210/jc.2003-031410. PMID 15070954.
- Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S (October 2001). "Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans". Diabetes 50 (10): 2199–202. doi:10.2337/diabetes.50.10.2199. PMID 11574398.
- Way JM, Görgün CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Willson TM, Kliewer SA, Hotamisligil GS (July 2001). "Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists". J. Biol. Chem. 276 (28): 25651–3. doi:10.1074/jbc.C100189200. PMID 11373275.
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.
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This family consists of several mammalian resistin proteins. Resistin is a 12.5-kDa cysteine-rich secreted polypeptide first reported from rodent adipocytes. It belongs to a multigene family termed RELMs or FIZZ proteins. Plasma resistin levels are significantly increased in both genetically susceptible and high-fat-diet-induced obese mice. Immunoneutralisation of resistin improves hyperglycemia and insulin resistance in high-fat-diet-induced obese mice, while administration of recombinant resistin impairs glucose tolerance and insulin action in normal mice. It has been demonstrated that increases in circulating resistin levels markedly stimulate glucose production in the presence of fixed physiological insulin levels, whereas insulin suppressed resistin expression. It has been suggested that resistin could be a link between obesity and type 2 diabetes .
Nogueiras R, Gallego R, Gualillo O, Caminos JE, Garcia-Caballero T, Casanueva FF, Dieguez C; , FEBS Lett 2003;548:21-27.: Resistin is expressed in different rat tissues and is regulated in a tissue- and gender-specific manner. PUBMED:12885401 EPMC:12885401
Maebuchi M, Machidori M, Urade R, Ogawa T, Moriyama T; , Arch Biochem Biophys 2003;416:164-170.: Low resistin levels in adipose tissues and serum in high-fat fed mice and genetically obese mice: development of an ELISA system for quantification of resistin. PUBMED:12893293 EPMC:12893293
This tab holds annotation information from the InterPro database.
InterPro entry IPR009714
This family consists of several mammalian resistin proteins. Resistin is a 12.5 kDa cysteine-rich secreted polypeptide first reported from rodent adipocytes. It belongs to a multigene family termed RELMs or FIZZ proteins. Plasma resistin levels are significantly increased in both genetically susceptible and high-fat-diet-induced obese mice. Immunoneutralisation of resistin improves hyperglycemia and insulin resistance in high-fat-diet-induced obese mice, while administration of recombinant resistin impairs glucose tolerance and insulin action in normal mice. It has been demonstrated that increases in circulating resistin levels markedly stimulate glucose production in the presence of fixed physiological insulin levels, whereas insulin suppressed resistin expression. It has been suggested that resistin could be a link between obesity and type 2 diabetes [PUBMED:12885401].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||extracellular region (GO:0005576)|
|Molecular function||hormone activity (GO:0005179)|
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Seed source:||Pfam-B_15476 (release 10.0)|
|Number in seed:||33|
|Number in full:||70|
|Average length of the domain:||80.60 aa|
|Average identity of full alignment:||53 %|
|Average coverage of the sequence by the domain:||68.14 %|
|HMM build commands:||
build method: hmmbuild --amino -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
|Download:||download the raw HMM for this family|
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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 More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Resistin domain has been found. There are 12 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.
Loading structure mapping...