When was adiponectin discovered

However, recent crystal structure of AdipoR1 suggest to broaden interface at the extracellular regions in addition to the flexible C-terminal tail [ 17 ]. These findings led us to identify the ligand-binding regions in AdipoR1 and to design each peptides as well as to simulate interaction between peptide and AdipoR1. Through several rounds of designing and screening, three mer peptides were selected. This study also provides an attractive time-efficient strategy to develop synthetic agonists for diseases-related membrane receptors, such as G-coupled protein receptors.

The adiponectin binding to AdipoR1 was analyzed with its recently reported crystal structure PDB ID: 3WXV and the configuration of the binding site was applied to the peptide binding simulation study.

The possible interaction configurations between AdipoR1 and the designed peptides were analyzed by using Maestro The clustering poses were obtained according to the ligand positions, followed by selection of the peptide binding pose that occupied the predicted binding cavities in the extracellular region of AdipoR1. The minimized protein-protein structures were analyzed to find important interactions.

After collecting information about non-bonding interaction, electrostatic interaction and hydrogen bond network between AdipoR1 and peptides, twenty five 25 peptides were selected and further screened by biophysical and biological assays. South Korea.

Lyophilized peptides were dissolved with distilled water to be more than 2 mM stock concentration, followed by dilution to working concentrations with an appropriate buffer. N-terminal site-specific mono-PEGylation of the selected peptides was accomplished by using PEG derivative through a reactive terminal aldehyde group as described by Na et. Tanabe et. Harvested cells were disrupted by dounce homogenization, followed by centrifugation at 30, rpm for 2 hours.

The resulting sensorgrams were double-blanked by reference cell and buffer injection. On the fifth day, differentiation of cells could be confirmed by multinucleated contracted myotubes. C2C12 myotubes were then treated with selected peptide candidates at indicated concentrations for 30 minutes. Signals from Western blot were quantified by using Image Lab Software 6. Human adiponectin receptor is a seven-transmembrane protein with N-terminal cytoplasmic domain, so AdipoR1 has three extracellular loops ECL and extracellular C-terminal region.

Biochemical evaluation results indicated that the C-terminal extracellular region is critical for ligand binding, but recent structural and mutational studies suggest that the conserved extracellular loop residues are also involved in adiponectin signaling [ 10 , 17 ].

In order to design a structure-based ligand, the docking site of the receptor must be precisely examined. The results of simulation study supported extended ligand binding interface formed by all extracellular loops and C-terminal region as suggested by previous study [ 17 ]. Considering oligomerization of adiponectin [ 21 ], it would be possible that two adiponectin molecules bind to one AdipoR1. The discovery of two opposite-direction binding sites provided invaluable information in designing a peptide library.

Adiponectin docking model. Two predicted ligand-binding regions were indicated by yellow colour. Sequence and structure of active region of adiponectin. C and D. Z-Dock protein-protein docking and refinement. Two binding regions C, site 1 and D, site 2 were separately presented with adiponectin active peptide sequence. Along with the active sequence information of the natural ligands, the local structure of predicted ligand-binding regions were examined.

They were subsequently evaluated from the perspective of binding capability of each peptide docks to AdipoR1 in a structurally and chemically complementary manner. Then the peptides were further assessed for physical interaction of the peptides to AdipoR1, and finally the selected peptides were evaluated by assessing the level of AdipoR1 phosphorylation on cells.

In assessing the physical interaction between AdipoR1 and the designed peptides, we applied surface plasmon resonance SPR method that provides kinetic information such as association and dissociation rates besides binding constants.

Shaded regions indicate transmembrane domain. Both constructs have N-terminal flag tag for further purification. Eluents were analyzed by Western blot with anti-flag and anti-AdipoR1 antibodies. While designing peptides, we observed two important factors. First, through docking simulation between ADP and AdipoR1, it was found that hydrophobic interaction near the C-terminal domain, especially F and Y, is crucial Fig 1C and 1D in both ligand-binding regions.

As a result, the focus of our design concept was narrowed down to a short but effective peptide. During the course of the study, we were also able to evaluate the SPR-based testing system for its potential standardized application for peptide screening.

This biophysical screening method using SPR allowed to evaluate binding affinity and binding quality of the candidates to AdipoR1 at the same time. A concentration-dependent experiment could give information on the extent of an efficient comparison of the binding affinities of the peptides to the target and minimize false positive hits. An SPR sensorgram itself provided much information to decide hit peptides.

Slower dissociation pattern may implicate better efficacy. In fact, among screened peptides, BHD showed the slowest dissociation in the sensorgram and the highest biological efficacy. In order to maintain the active conformation of the transmembrane protein, DDM and CHS were introduced in immobilization and running buffers.

This discrepancy might imply inappropriate in vitro system due to artificial environment, such as immobilization of membrane protein on the chip, which differs from cellular membrane. However, some designed peptides showed higher responses in a concentration-dependent response pattern. Moreover, some designed peptides showed slower dissociation rate than ADP The Kd values of the selected peptides were calculated from saturation curves with responses at equilibrium state.

Among the three peptides, BHD44 showed the lowest Kd value of 4. SPR signals from different concentrations were plotted against concentrations to calculate Kd value. Docking simulation of the selected peptides onto AdipoR1 was followed in order to evaluate their interaction. Based on this simulation, we discovered that each ligand-binding region was further divided into two pockets, resulting in four major binding pockets Fig 4.

All pockets were mainly composed of hydrophobic residues: pocket 1 was composed of L, Y, and Y; pocket 2 was composed of Y and Y; pocket 3 was composed of K and F; pocket 4 was composed of F and F Fig 4. BHD is expected to bind to all four major pockets Fig 4A. The N-terminal Tyr and the third Phe of BHD could form hydrophobic interaction with the pocket 1 and 2, respectively. The 13 th Tyr and the 15 th Phe could also form hydrophobic interaction with the pocket 3 and 4, respectively.

Also, the 7 th Pro and the C-terminal carbonyl group of BHD may form hydrogen bond with the side chain of N and S, respectively. Four major binding pockets were indicated with arched lines. Pocket 1 and 2 formed ligand binding site 2 and pocket 3 and 4 formed ligand binding site 1.

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Weyer, C. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. However, starting in , several studies were published from different laboratories that highlighted the potential antidiabetic, antiatherosclerotic and anti-inflammatory properties of this protein complex.

Methods to measure the protein with high throughput assays in clinical samples were developed shortly thereafter, and as a result hundreds of clinical studies have been published over the past 3 years describing the role of adiponectin in endocrine and metabolic dysfunction. Furthermore, adiponectin research has expanded to include a role for adiponectin in cancer and other disease areas.