Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein

Takahashi-Íñiguez, Tóshiko; Garcı́a-Arellano, Humberto; Trujillo‐Roldán, Mauricio A.; Flores, María Elena

doi:10.1016/j.bbrc.2010.11.141

Cited by 33 publications

(23 citation statements)

References 17 publications

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“…Here, we observe the same open and closed conformations of the TIM barrel, but the correlation is with the absence/presence of Cbl in the barrel as neither structure has substrate. Although the key role of the G-protein metallochaperone must be in AdoCbl loading, MeaB and MMAA also reduce the rate of inactivation of their target enzyme MCM at no cost to catalytic efficiency (6,18). It is tempting to consider that this protection arises from the G protein assisting conformational changes of the TIM barrel to prevent formation of inactive enzyme states.…”

Section: The G-protein Active Site Undergoes Nucleotide-sensitive Conmentioning

confidence: 99%

“…One important group of metallochaperones comprises the small guanine nucleotide-binding proteins (G proteins) belonging to the SIMIBI class (after signal recognition particle, MinD, and BioD) of P-loop NTPases (4). The human G-protein chaperone, MMAA (methylmalonic aciduria type A protein, mitochondrial; gene product of cblA), is involved in the assembly of adenosylcobalamin (AdoCbl, coenzyme B 12 )-dependent methylmalonyl-CoA mutase (MCM) (5,6). Mutations in MMAA and MCM result in methylmalonic aciduria, a genetically inherited metabolic disease that is devastating in newborns and infants (7).…”

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confidence: 99%

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Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Jost¹,

Cracan

Hubbard³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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G-protein metallochaperones ensure fidelity during cofactor assembly for a variety of metalloproteins, including adenosylcobalamin (AdoCbl)-dependent methylmalonyl-CoA mutase and hydrogenase, and thus have both medical and biofuel development applications. Here, we present crystal structures of IcmF, a natural fusion protein of AdoCbl-dependent isobutyryl-CoA mutase and its corresponding G-protein chaperone, which reveal the molecular architecture of a G-protein metallochaperone in complex with its target protein.These structures show that conserved G-protein elements become ordered upon target protein association, creating the molecular pathways that both sense and report on the cofactor loading state. Structures determined of both apo-and holo-forms of IcmF depict both open and closed enzyme states, in which the cofactor-binding domain is alternatively positioned for cofactor loading and for catalysis. Notably, the G protein moves as a unit with the cofactorbinding domain, providing a visualization of how a chaperone assists in the sequestering of a precious cofactor inside an enzyme active site.

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Section: The G-protein Active Site Undergoes Nucleotide-sensitive Conmentioning

confidence: 99%

mentioning

confidence: 99%

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Jost¹,

Cracan

Hubbard³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Thus, in the presence of either GDP or GTP, MeaB slows the rate of MCM inactivation by 30-fold (28), and the exchange of GDP for GTP drives the ejection of inactive cofactor from the active site of MCM. The limited biochemical studies support a role for CblA that is analogous to the better characterized bacterial MeaB in protecting MCM from inactivation and rescuing inactive MCM (37). Furthermore, human MCM also exhibits GAP activity with respect to CblA (29).…”

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confidence: 99%

Autoinhibition and Signaling by the Switch II Motif in the G-protein Chaperone of a Radical B12 Enzyme

Lofgren

Koutmos

Banerjee

2013

Journal of Biological Chemistry

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Background: MeaB is a G-protein chaperone of methylmalonyl-CoA mutase (MCM). Results: Mutations in the canonical switch II motif disrupt signaling in the MeaB-MCM complex. Conclusion:The switch II loop is autoinhibitory for the intrinsic GTPase activity of MeaB. Significance: Signaling in the MeaB-MCM complex is achieved via nucleotide-dependent conformational coupling between switches II and III.

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“…MeaB diminishes the inactivation rate of the mutase ϳ15-and ϳ3-fold in the presence of GTP and GDP, respectively (20). The human ortholog of MeaB is CblA and it is reported to prevent inactivation and increase the enzymatic activity of human MCM (38,39). In IcmF, which has a built-in G-protein chaperone, GTP and GDP protect against inactivation in wild-type but not in F598A IcmF (Fig.…”

Section: Discussionmentioning

confidence: 94%

Engineered and Native Coenzyme B12-dependent Isovaleryl-CoA/Pivalyl-CoA Mutase

Kitanishi

Cracan

Banerjee

2015

Journal of Biological Chemistry

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Background: IcmF exhibits low isovaleryl-CoA/pivalyl-CoA mutase (PCM) activity. Results: IcmF mutants designed to enhance PCM activity were susceptible to inactivation prompting a bioinformatics search for a "bona fide" PCM. Conclusion: A B 12 -dependent PCM was identified, cloned, and expressed and exhibited PCM activity. Significance: The newly discovered PCM could be useful in bioremediation and biosynthetic reactions.

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Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein

Cited by 33 publications

References 17 publications

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Autoinhibition and Signaling by the Switch II Motif in the G-protein Chaperone of a Radical B12 Enzyme

Engineered and Native Coenzyme B12-dependent Isovaleryl-CoA/Pivalyl-CoA Mutase

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Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein

Cited by 33 publications

References 17 publications

Visualization of a radical B 12 enzyme with its G-protein chaperone

Visualization of a radical B 12 enzyme with its G-protein chaperone

Autoinhibition and Signaling by the Switch II Motif in the G-protein Chaperone of a Radical B12 Enzyme

Engineered and Native Coenzyme B12-dependent Isovaleryl-CoA/Pivalyl-CoA Mutase

Contact Info

Product

Resources

About

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone

Visualization of a radical B ₁₂ enzyme with its G-protein chaperone