ESPE2022 Poster Category 1 Fat, Metabolism and Obesity (73 abstracts)
Background: In an effort to better understand the molecular basis of obesity, studies focus on genetic loci mapping to the leptin–melanocortin pathway, one of the key mechanisms for controlling food intake and body weight. Adenylate cyclase 3 (ADCY3) is a key genetic candidate as it seems to have an essential role at primary neuronal cilia in regulating body weight. We have previously reported the novel probably pathogenic ADCY3 variant c.349T>A identified in young obese patients of Cypriot origin. In the present study we use molecular modelling to demonstrate that this variant causes a p.Leu117Met substitution in within one of the two pseudo-symmetric halves of the transmembrane part of the protein.
Methods: To investigate the possible effects of the novel p.Leu117Met variation on protein structure and function, the homology modelling of the ADCY3 model was carried out using Molecular Operating Environment. The electrostatic potential and available conformational space was calculated for both wild type and mutant models. Bonding interactions within the protein structure as well as with the surrounding lipid bilayer were studied.
Results: Molecular modelling data suggest a change in interactive forces and energy levels, probably affecting the pseudo-twofold symmetry of the transmembrane domain of the protein and its interaction with the surrounding lipid bilayer. This may be the result of stronger H-bonding interactions between the Met residue and adjacent residues, compared to the wild type Leu residue. The data suggest a change in the interaction of the two transmembrane halves of the enzyme which may possibly alter its catalytic function.
Conclusion: Our findings contribute to existing evidence linking ADCY3 to obesity development. Further assessment of this variant using functional studies, should help elucidate its clinical significance and role in obesity development.
15 Sep 2022 - 17 Sep 2022