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.