Non-synonymous single nucleotide polymorphisms of ATG5 destabilize ATG12-ATG5/ATG16L1 complex: An enzyme with E3 like activity of ubiquitin conjugation system

- 3 nsSNPs predicted in ATG5 pose deleterious impact on its protein.
- ConSurf analysis revealed the conservation profile of predicted nsSNPs in ATG5.
- M129V mutation leads to gain in Lysine methylation that may hinder ATG5 interactions.
- The nsSNPs destabilize ATG12-ATG5/ATG16L1 complex by decreasing the total energy.
- Binding affinity of ATG12-ATG5/ATG16L1 complex components decreases upon mutations.

ATG5 is an essential autophagy related protein that acts as an E3-like activating enzyme of ubiquitin-like conjugating system in conjunction with ATG12 and ATG16L1. The ATG12-ATG5/ATG16L1 complex is an essential complex which is crucial for autophagosome biogenesis. In this work, we have studied the impact of nsSNPs of ATG5 (rs34793250, rs77859116 and rs115576116) over protein structure. Mutant structures were generated for these variations, singly and in combinations for computation of total energy using CHARMM force field. These nsSNPs result into significant deviations in mutant structures. Although, all three mutations increased total energy of the protein complex but the mutation M129V was found to increase total energy to maximum compared to the native structure and we conclude that it is the most destabilizing mutation predicted in ATG5. Furthermore, these nsSNPs decreased the binding affinity of ATG5 with ATG12 and ATG16L1. Thus, the predicted nsSNPs in ATG5 likely exert a strong impact on protein structure that may destabilize the complex or decrease its binding affinity which could aid in disease pathogenesis by deregulating autophagy. These nsSNPs could be targeted to elucidate the mechanisms of autophagy related disorders and to find their association with various diseases where deregulation of this process is involved.