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FUNCTION
The protein adiponectin receptor 1 is one of the two receptors for the hormone called adiponectin. The adiponectin is an hormone, and more precisely an adipokine <ref name="doc1">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.[3], present in the blood at high concentration, approximatively 0,01 % of the total amount of proteins in plasma. The human adiponectin monomer as molecular weight of about 28 kDa and is composed of 244 amino acids. However, the molecular weight of the hormone depends on the multimerization of this one. The hormone is mainly created by adipocytes present in white and brown adipose tissues but some studies manifest that it could be produced in some non-adipose tissues as in skeletal muscle. Two forms of adiponectin exist: the full-length adiponectin, presents in the liver and the globular adiponectin presents in skeletal muscles and in the liver. The adiponectin receptor 1 is a receptor for the globular form. This hormone is known to be anti-diabetic, antiatherogenic and a regulator of tissue inflammation and insulin sensitivity. These properties of the adiponectin are linked to the fatty oxidation trigger by the hormone and the adipoR1 receptor. Different fatty acid oxidation pathway exists. The major pathway regulated by adipoR1 is the AMP kinase channel, but this pathway is not completely known. However, several studies show that adipoR1 decreases the hepatic glucose production by activating this channel. AdipoR1 is also able to limit the expression of enzymes, like glucose-6-phosphatase, phosphoenolpyruvate carboxykinase and carboxykinase1, involved in gluconeogenesis.
STRUCTURE
The Adiponectin receptor 1 is an integral membrane protein composed of 375 amino acids and its molecular weight is 42,4 kDa. This protein can be decomposed into different parts: an internal N-terminus domain (residues 89 to 120), a short intracellular domain called helix 0 (residues 121 to 129), seven transmembrane helices (residues 134 to 364) and an external C-terminus domain (residues 365 to 375).
The organisation of the structure of the Adiponectin receptor 1 is the opposite to G protein-coupled receptor family. Indeed, the Adiponectin receptor has an internal N-terminus domain and an external C-terminus domain while the G-protein family has an internal N-terminus domain and an external C-terminus domain.
The Adiponectin receptor 1 contains seven transmembrane helices linked thanks to three extracellular loops and three intracellular loops. The helix I is formed by the residues 135 to 157, helix II by the residues 169 to 192, the helix III by the residues 198 to 227, the helice IV by the residues 232 to 252, the helix V by the residues 264 to 288 heliX VI by the residues 305 to 319 and the helix VII by the residues 336 to 364 .Besides, the helix III and VII are longer than the other helices. These seven transmembrane helices have a clockwise circular specific organisation (from helix I to helix VII) and form a bundle.
Concerning the extracellular faces, the three extracellular loops which connect the transmembrane helices are exposed and it is the same for the C-terminus domain. Besides, helix III and the VII are longer than the other helices and as a result the C-terminus domain two turns of the VII are exposed too.
In the middle of the seven transmembrane helices there is a large internal cavity where a zinc-binding site can be found. This cavity located from the cytoplasmic surface to the middle of the outer lipid layer of the membrane has small openings between the helix V and VI, and between the helice IV and VI. 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 H191 in the helix II, H337 and H341 in the helix VII. 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 helix II, III and VII 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.
AdipoR1 has the capacity to form oligomers. 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 helix V. 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.
Diseases
- ↑ 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:https://dx.doi.org/10.1002/ijch.201300024
- ↑ 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
- ↑ Cite error: Invalid
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