Structural insights into human propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC)

Abstract

Propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC) are biotin-dependent carboxylases (BDCs) that catalyze the metabolism of odd-chain fatty acids, cholesterol, and specific amino acids. For human PCC and MCC, only a low-resolution (15 Å) three-dimensional structure of human PCC has been reported. Here, we report high-resolution (2.29–3.28 Å) cryo-EM structures of human PCC and MCC holoenzymes in their apo and acetyl-CoA and propionyl-CoA-bound states. Propionyl-CoA and acetyl-CoA bind to PCC with almost identical binding modes, indicating that the acyl-CoA specificity of PCC is largely attributed to minor differences in interactions mediated by the acyl groups. In MCC, biotin is relocated from an exo-site to an endo-site upon acetyl-CoA binding, suggesting coordination between biotin binding and acyl-CoA binding. Our work provides insights into the substrate specificity and catalytic process of BDCs.