3.3.4 Dihydrolipoyl dehydrogenase loses connectivity away from the binding site.
The human mitochondrial dihydrolipoyl dehydrogenase (DLD, hE3 or E3) along with pyruvate dehydrogenase (E1) and dihydrolipoyl transacetylase (E2) form the pyruvate dehydrogenase complex (PDC) which is known to link the glycolysis metabolic pathway with the citric acid cycle. The primary function of the complex is to convert pyruvate to acetyl-CoA which is necessary for cellular respiration. The DLD protein exists as a homodimer, where each subunit consists of a FAD and NAD binding domain along with a central and an interface domain that interacts with the E3 binding protein (E3BP) to form the PDC. At the FAD binding domain active site, Flavin mediated oxidation takes place to oxidise the substrate which is reversed to FAD resting state using NAD+resulting in NADH and H. Deficiency of this protein is associated with autosomal recessive metabolic disorders.
In this case, the E3 homodimer is bound to E3 binding domain of E3BP forming a subcomplex with a strong hydrophobic interface (PDB ID 1ZY8 shown in Supplementary Figure 3D). It is reported that the central hydrophobic patch along with numerous ionic and hydrogen bonds between residues of the three chains add to the stability of the subcomplex. The network dissimilarity between the bound and the unbound form of this protein is found to be very high. A significant loss in the number of edges, mostly far from the site of the interface is observed (Figure 2D). While 19 hubs are lost all around the protein only three hubs are gained leading to a net severe loss of connectivity.