Figure 3.

Modeled structure of human mitochondrial ADP-forming succinyl-CoA synthetase with labeled pathogenic mutations (a). α subunit: light green; β subunit: cyan; catalytic His299: red; phosphohistidine loop: orange. Dashed arrow: tentative movement of the phosphohistidine loop between active sites. Decomposition of succinyl-CoA onto succinate and CoA in the catalytic α-subunit requires participation of a phosphate ion, which is coordinated by the N-termini of the two ‘power' helixes: one from the α-subunit and the other from the β-subunit. This phosphate is utilized for phosphorylation of the catalytic His299 (His246 in E. coli) of the α-subunit located in the phosphohistidine loop.¹⁴ Phosphorylation of ADP takes place in the active site of the β-subunit. The movement of the phosphohistidine loop with phosphorylated catalytic histidine has been suggested to shuttle the phosphate between the active sites of both subunits.^{14, 15} The missing fragment in the case of skipping of exon 6 and part of exon 7, encompassing residues 221–267, contains Glu256, a critical residue for ADP phosphorylation.²¹ Location of Asp333, a part of ‘power' helix β and the interface between subunits, within the modeled human mitochondrial SCS-A (b). Hydrogen bonds formed by Asp333: black dashed lines. Location of Arg284 and Asp251 within the modeled human SCS-A (c). Arg284 localizes to the interface between two subunits and forms a number of contacts with neighboring residues (Ser281, Asp251 and Asp151). Non-covalent bonds formed by Arg284: black dashed lines. Location of Gly118 and Ala103, in the ADP-binding site, with respect to bound ADP and the phosphohistidine loop (yellow) of subunit α of SCS-A (d).