CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

Lee, Jane K.J.; Liu, Yuntao; Hu, Jason J.; Aphasizheva, Inna; Aphasizhev, Ruslan; Zhou, Z. Hong

doi:10.1016/j.yjsbx.2023.100088

Cited by 2 publications

(2 citation statements)

References 54 publications

(70 reference statements)

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“…1B), suggesting that α-trimers could be more flexible than the β-core. This may also indicate that α-subunits assemble on the MCC barrel at a later stage, as shown for the PCC enzyme (Lee et al 2023), supported by observation of pre-formed β-hexamers particles with only one α-trimer in negative-stain grids (Fig. S1).…”

Section: Resultssupporting

confidence: 64%

The cryo-EM structure of trypanosome 3-methylcrotonyl-CoA carboxylase provides mechanistic and dynamic insights into enzymatic function

Plaza-Pegueroles,

Aphasizheva,

Aphasizhev

et al. 2023

Preprint

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Abstract3-methylcrotonyl-CoA carboxylase (MCC) catalyzes the two-step, biotin-dependent production of 3-methylglutaconyl-CoA, an essential intermediate in leucine catabolism. Given its critical metabolic role, deficiencies in this enzyme associate with organic aciduria, while its overexpression is linked to tumor development. MCC is a dodecameric enzyme composed of six copies of each α- and β-subunit. We present the cryo-EM structure of the endogenous MCC holoenzyme fromTrypanosoma bruceiin its soluble, non-filamentous state at 2.5 Å resolution. We unambiguously observe the position of biotin, covalently-bound to the BBCP domain of α-subunits and occupying a novel binding pocket next to the active site of a neighboring β-subunit dimer. Moreover, flexibility of key residues at the α/α- and α/β-subunit interfaces enables pivoting of α-subunit trimers to sequentially approach the otherwise distant active sites for the two steps in MCC catalysis. Our results provide a structural framework to understand the enzymatic mechanism of eukaryotic MCCs and assist drug discovery against trypanosome infections.

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Section: Resultssupporting

confidence: 64%

The cryo-EM structure of trypanosome 3-methylcrotonyl-CoA carboxylase provides mechanistic and dynamic insights into enzymatic function

Plaza-Pegueroles,

Aphasizheva,

Aphasizhev

et al. 2023

Preprint

Self Cite

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“…Several three-dimensional structures of PCCs and MCCs have been reported ( 12-18 ), however, most of them are from bacteria and expressed in E. coli(12-16) . In our study, we extracted the endogenous PCC and MCC from human cells by one-step affinity purification (fig.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou,

Zhang,

Zhu

et al. 2024

Preprint

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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.

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CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

Cited by 2 publications

References 54 publications

The cryo-EM structure of trypanosome 3-methylcrotonyl-CoA carboxylase provides mechanistic and dynamic insights into enzymatic function

The cryo-EM structure of trypanosome 3-methylcrotonyl-CoA carboxylase provides mechanistic and dynamic insights into enzymatic function

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

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