Discovery, structure, and function of filamentous 3-methylcrotonyl-CoA carboxylase

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

doi:10.1016/j.str.2022.11.015

Cited by 16 publications

(9 citation statements)

References 74 publications

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“…To capture cryoEM structures of various biotin-binding complexes, we performed streptavidin pull-down of endogenous complexes from L. tarentolae mitochondrial lysate fractionated by glycerol density gradient and determined their structures. One subset of these structures has a three-fold symmetric architecture reminiscent of carboxylases ( Huang et al, 2010 , Tong, 2013 , Huang et al, 2012 , Jurado et al, 2015 , Hu et al, 2023 ); by using the cryoID approach ( Ho et al, 2020 ), we confirmed its identity as propionyl-CoA carboxylase from L. tarentolae (LtPCC).…”

Section: Resultsmentioning

confidence: 82%

CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

Lee¹,

Liu²,

Hu³

et al. 2023

Journal of Structural Biology: X

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Section: Resultsmentioning

confidence: 82%

CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

Lee¹,

Liu²,

Hu³

et al. 2023

Journal of Structural Biology: X

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“…Several three-dimensional structures of PCCs and MCCs have been reported (12)(13)(14)(15)(16)(17)(18), however, most of them are from bacteria and expressed in E. coli (12)(13)(14)(15)(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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“…An equivalent architecture has been found in the electron cryomicroscopy (cryo-EM) structure of MCC from the eukaryote Leishmania tarentolae (LtMCC), forming straight filaments composed by four to six dodecameric MCC barrels connected though α-subunit trimers (Hu et al 2023). In this structure, the BT-BCCP linker is partially fixed through an interaction with the N-dock domain of a neighboring β-subunit, which hampers the BCCP domain to reach the α-subunit active site.…”

Section: Introductionmentioning

confidence: 92%

“…Additionally, biotin is not found attached covalently to lysine in the BCCP domain in the filaments. These two features suggest that the LtMCC structure represents an inactive state of this enzyme (Hu et al 2023).…”

Section: Introductionmentioning

confidence: 99%

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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Discovery, structure, and function of filamentous 3-methylcrotonyl-CoA carboxylase

Cited by 16 publications

References 74 publications

CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

CryoEM reveals oligomeric isomers of a multienzyme complex and assembly mechanics

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

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

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