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In the middle of the seven transmembrane helices there is a large internal cavity extended from the cytoplasmic surface to the outer lipid layer where a <scene name='82/829353/Zinc-binding_site/2'>zinc-binding site</scene> can be found. This cavity has small openings between the <scene name='82/829353/Helice5/2'>helix V</scene> and <scene name='82/829353/Helix6/2'>VI</scene>, and between the <scene name='82/829353/Helix4/2'>helice IV</scene> and <scene name='82/829353/Helix6/2'>VI</scene>. It has been assumed that these openings are involved in the entrance and exit of both substrate and product.
In the middle of the seven transmembrane helices there is a large internal cavity extended from the cytoplasmic surface to the outer lipid layer where a <scene name='82/829353/Zinc-binding_site/2'>zinc-binding site</scene> can be found. This cavity has small openings between the <scene name='82/829353/Helice5/2'>helix V</scene> and <scene name='82/829353/Helix6/2'>VI</scene>, and between the <scene name='82/829353/Helix4/2'>helice IV</scene> and <scene name='82/829353/Helix6/2'>VI</scene>. It has been assumed that these openings are involved in the entrance and exit of both substrate and product.
In this cavity, there is a zinc ion which is coordinated thanks to three histidine residues. These three histidine residues are <scene name='82/829353/H191/2'>H191</scene> in the <scene name='82/829353/Helix2/2'>helix II</scene>, <scene name='82/829353/H337/2'>H337</scene> and <scene name='82/829353/H341/2'>H341</scene> in the <scene name='82/829353/Helix7/2'>helix VII</scene>. As a result, the zinc ion is in the intracellular layer of the membrane, in the neighbourhood of 4° deep from the inner surface of the plasma membrane. Thanks to its tetrahedral coordination, this zinc ion binds the <scene name='82/829353/Helix2/2'>helix II</scene>, <scene name='82/829353/Helix3/2'>III</scene> and <scene name='82/829353/Helix7/2'>VII</scene> together. The adiponectin-stimulated AMPK phosphorylation doesn’t directly require the zinc binding site, nevertheless it has been supposed that the zinc ion allows a stabilizing effect. <ref name="doc1"/>
In this cavity, there is a zinc ion which is coordinated thanks to three histidine residues. These three histidine residues are <scene name='82/829353/H191/2'>H191</scene> in the <scene name='82/829353/Helix2/2'>helix II</scene>, <scene name='82/829353/H337/2'>H337</scene> and <scene name='82/829353/H341/2'>H341</scene> in the <scene name='82/829353/Helix7/2'>helix VII</scene>. As a result, the zinc ion is in the intracellular layer of the membrane, in the neighbourhood of 4° deep from the inner surface of the plasma membrane. Thanks to its tetrahedral coordination, this zinc ion binds the <scene name='82/829353/Helix2/2'>helix II</scene>, <scene name='82/829353/Helix3/2'>III</scene> and <scene name='82/829353/Helix7/2'>VII</scene> together. The adiponectin-stimulated AMPK phosphorylation doesn’t directly require the zinc binding site, nevertheless it has been supposed that the zinc ion allows a stabilizing effect. <ref name="doc1"/>
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AdipoR1 has the capacity to form [http://en.wikipedia.org/wiki/Oligomer oligomers]. <ref name="doc3"> Takashi Kadowaki and Toshimasa Yamauchi et al. « Adiponectin and adiponectin receptors». https://www.ncbi.nlm.nih.gov/pubmed/15897298</ref> Indeed in living cell both monomers and oligomers are present. A specific motif was identified to contribute to the AdipoR1 dimerization: it is the motif GxxxG in the transmembrane <scene name='82/829353/Helice5/2'>helix V</scene>. Besides, the dimerization of AdipoR1 is also regulated. This dimerization is inhibited by the fixation of the full-length adiponectin while the globular adiponectin has any impact on the dimerization level of the AdipoR1 receptor. Thanks to mutant experiment, it can be supposed that the collagen-like domain of the full-length adiponectin is responsible to the dimer dissociation. There are strong evidences that dimerization of the AdipoR1 receptor has a role during the biosynthesis, the trafficking and the signalling of the seven transmembrane receptors. <ref name="doc4"> Kosel D, Heiker JT, Juhl C, Wottawah CM, Blüher M, Mörl K, Beck-Sickinger AG et al. « Dimerization of adiponectin 1 is inhibited by adiponectin » Journal of Cell Science 123, 1320-1328 (2010) : https://www.ncbi.nlm.nih.gov/pubmed/20332107</ref>
AdipoR1 has the capacity to form [http://en.wikipedia.org/wiki/Oligomer oligomers]. <ref name="doc3"> Takashi Kadowaki and Toshimasa Yamauchi et al. « Adiponectin and adiponectin receptors». https://www.ncbi.nlm.nih.gov/pubmed/15897298</ref> Indeed in living cell both monomers and oligomers are present. A specific motif was identified to contribute to the AdipoR1 dimerization: it is the motif GxxxG in the transmembrane <scene name='82/829353/Helice5/2'>helix V</scene>. Besides, the dimerization of AdipoR1 is also regulated. This dimerization is inhibited by the fixation of the full-length adiponectin while the globular adiponectin has any impact on the dimerization level of the AdipoR1 receptor. Thanks to mutant experiment, it can be supposed that the collagen-like domain of the full-length adiponectin is responsible to the dimer dissociation. There are strong evidences that dimerization of the AdipoR1 receptor has a role during the biosynthesis, the trafficking and the signalling of the seven transmembrane receptors. <ref name="doc4"> Kosel D, Heiker JT, Juhl C, Wottawah CM, Blüher M, Mörl K, Beck-Sickinger AG et al. « Dimerization of adiponectin 1 is inhibited by adiponectin » Journal of Cell Science 123, 1320-1328 (2010) : https://www.ncbi.nlm.nih.gov/pubmed/20332107</ref>
== Diseases ==
== Diseases ==
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AdipoR1 is involved in different diseases and symptoms. One major diseases linked with this proteine is the [http://en.wikipedia.org/wiki/Type_2_diabetes Type II diabete] which is caracterized by a chronic hyperglycemia. This disease is mainly present in obese or overweight people. In case of type II diabete, adiponectin level in plasma is reduced signficantly and the expression of the adiponectin receptors,AdipoR1, decreases, especially in [http://en.wikipedia.org/wiki/Skeletal_muscle skeletal muscle] and [http://en.wikipedia.org/wiki/Adipose_tissue adipose tissues] .<ref name="doc3"/> <ref name="doc7"/>
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AdipoR1 is involved in different diseases and symptoms. One major diseases linked with this proteine is the [http://en.wikipedia.org/wiki/Type_2_diabetes '''Type II diabete'''] which is caracterized by a chronic hyperglycemia. This disease is mainly present in obese or overweight people. In case of type II diabete, adiponectin level in plasma is reduced signficantly and the expression of the adiponectin receptors,AdipoR1, decreases, especially in [http://en.wikipedia.org/wiki/Skeletal_muscle skeletal muscle] and [http://en.wikipedia.org/wiki/Adipose_tissue adipose tissues] .<ref name="doc3"/> <ref name="doc7"/>
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Another symptom linked to adipoR1 is the insulin resistance. An [http://en.wikipedia.org/wiki/Insulin_resistance insulin resistant] organism is an organism which will require more insulin to obtain the biological effects of a normal organism<ref name="doc8"/>.Insulin resistance can be caused by any defects in the insulin signaling cascade, including problems with AdipoR1<ref name="doc8"/>.[http://en.wikipedia.org/wiki/Hyperglycemia Hyperglycemia] and [http://en.wikipedia.org/wiki/Hyperinsulinemia hyperinsulinemia] are probably the cause of insulin resistance<ref name="doc3"/>. In fact, The adiponectin levels and the expression of AdipoR1 drop, reducing adiponectin sensitivity and so lead to insulin resistance<ref name="doc8"/>.
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Another symptom linked to adipoR1 is the '''insulin resistance'''. An [http://en.wikipedia.org/wiki/Insulin_resistance insulin resistant] organism is an organism which will require more insulin to obtain the biological effects compare to a normal organism<ref name="doc8"/>.Insulin resistance can be caused by any defects in the insulin signaling cascade, including problems with AdipoR1<ref name="doc8"/>.[http://en.wikipedia.org/wiki/Hyperglycemia Hyperglycemia] and [http://en.wikipedia.org/wiki/Hyperinsulinemia hyperinsulinemia] are probably the cause of insulin resistance<ref name="doc3"/>. In fact, The adiponectin levels and the expression of AdipoR1 drop, reducing adiponectin sensitivity and so lead to insulin resistance<ref name="doc8"/>. Then, insulin resistance provoque a drop of adiponectin secretion and circulation level, increasing hyperinsulinemia.This is the start of a vicious cycle<ref name="doc7"/> <ref name="doc3"/>.
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Then, insulin resistance provoque a drop of adiponectin secretion and circulation level, increasing hyperinsulinemia.This is the start of a vicious cycle<ref name="doc7"/> <ref name="doc3"/>.
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Obesity and insulin resistance also lead to [http://en.wikipedia.org/wiki/Metabolic_syndrome metabolic syndrome].Indeed,adipoR1 can display metabolic dysfunction, especially in case of the drop of its expression<ref name="doc5"/>.However agonist of adiponectin receptor (AdipoR1) should be a new treatment strategie for metabolic syndrome or obesity-linked diseases<ref name="doc3"/>.Moreover,a treatment against type II diabete and insulin resistance could be AdipoR1 overexpression, which improves insulin resistance and promotes glucose uptake in skeletal muscle in one hand, and attenuates weight gain and improves glucose metabolism models of metabolic dysfunction in macrophages in the other hand<ref name="doc5"/>.
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Obesity and insulin resistance also lead to [http://en.wikipedia.org/wiki/Metabolic_syndrome '''metabolic syndrome'''].Indeed,adipoR1 can display metabolic dysfunction, especially in case of the drop of its expression<ref name="doc5"/>.However agonist of adiponectin receptor 1 should be a new treatment strategie for metabolic syndrome or obesity-linked diseases<ref name="doc3"/>.Moreover,a treatment against type II diabete and insulin resistance could be AdipoR1 overexpression. It could,in the one hand, improves insulin resistance and promotes glucose uptake in skeletal muscle,and, in the other hand, attenuates weight gain and improves glucose metabolism models of metabolic dysfunction in macrophages<ref name="doc5"/>.
== 3D visualisation ==
== 3D visualisation ==
Use of Jsmol and Jmol <ref>DOI 10.1002/ijch.201300024</ref><ref>PMID:21638687</ref>
Use of Jsmol and Jmol <ref>DOI 10.1002/ijch.201300024</ref><ref>PMID:21638687</ref>
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</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

Current revision

This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115.
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The Adiponectin receptor 1

Adiponectin receptor 1 (AdipoR1) structure

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References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Tanabe, Hiroaki, Yoshifumi Fujii, Miki Okada-Iwabu, Masato Iwabu, Yoshihiro Nakamura, Toshiaki Hosaka, Kanna Motoyama, et al. « Crystal structures of the human adiponectin receptors ». Nature 520, nᵒ 7547 (1 avril 2015): 312‑16. https://doi.org/10.1038/nature14301
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Kadowaki, Takashi et al. “Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.” The Journal of clinical investigation vol. 116,7 (2006): 1784-92. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483172/
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Whitehead, J. P., A. A. Richards, I. J. Hickman, G. A. Macdonald, et J. B. Prins. « Adiponectin – a Key Adipokine in the Metabolic Syndrome ». Diabetes, Obesity and Metabolism 8, nᵒ 3 (2006): 264‑80. https://doi.org/10.1111/j.1463-1326.2005.00510.x.
  4. ↑ 4.0 4.1 Yamauchi, Toshimasa, Junji Kamon, Yusuke Ito, Atsushi Tsuchida, Takehiko Yokomizo, Shunbun Kita, Takuya Sugiyama, et al. « Cloning of adiponectin receptors that mediate antidiabetic metabolic effects ». Nature 423, nᵒ 6941 (1 juin 2003): 762‑69. https://doi.org/10.1038/nature01705.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Takashi Kadowaki and Toshimasa Yamauchi et al. « Adiponectin and adiponectin receptors». 2015 https://www.ncbi.nlm.nih.gov/pubmed/15897298
  6. ↑ 6.0 6.1 6.2 Parker-Duffen JL, Nakamura K, Silver M, Zuriaga MA, MacLauchlan S, Aprahamian TR, Walsh K et al. «Divergent roles for adiponectin receptor 1 (AdipoR1) and AdipoR2 in mediating revascularization and metabolic dysfunction in vivo.» 17 April 2014 : https://www.ncbi.nlm.nih.gov/pubmed/24742672
  7. ↑ Kosel D, Heiker JT, Juhl C, Wottawah CM, Blüher M, Mörl K, Beck-Sickinger AG et al. « Dimerization of adiponectin 1 is inhibited by adiponectin » Journal of Cell Science 123, 1320-1328 (2010) : https://www.ncbi.nlm.nih.gov/pubmed/20332107
  8. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  9. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
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