NDLI: Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Yamada, Kazuhiro Gherasim, Carmen Banerjee, Ruma Koutmos, Markos
Description	Author Affiliation: Yamada K ( From the Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 and.); Gherasim C ( the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0600.); Banerjee R ( the Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0600 rbanerje@umich.edu.); Koutmos M ( From the Department of Biochemistry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 and markos.koutmos@usuhs.edu.)
Abstract	In mammals, B12 (or cobalamin) is an essential cofactor required by methionine synthase and methylmalonyl-CoA mutase. A complex intracellular pathway supports the assimilation of cobalamin into its active cofactor forms and delivery to its target enzymes. MMADHC (the methylmalonic aciduria and homocystinuria type D protein), commonly referred to as CblD, is a key chaperone involved in intracellular cobalamin trafficking, and mutations in CblD cause methylmalonic aciduria and/or homocystinuria. Herein, we report the first crystal structure of the globular C-terminal domain of human CblD, which is sufficient for its interaction with MMADHC (the methylmalonic aciduria and homocystinuria type C protein), or CblC, and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an +ß fold that is structurally reminiscent of the nitro-FMN reductase superfamily. Two of the closest structural relatives of CblD are CblC, a multifunctional enzyme important for cobalamin trafficking, and the activation domain of methionine synthase. CblD, CblC, and the activation domain of methionine synthase share several distinguishing features and, together with two recently described corrinoid-dependent reductive dehalogenases, constitute a new subclass within the nitro-FMN reductase superfamily. We demonstrate that CblD enhances oxidation of cob(II)alamin bound to CblC and that disease-causing mutations in CblD impair the kinetics of this reaction. The striking structural similarity of CblD to CblC, believed to be contiguous in the cobalamin trafficking pathway, suggests the co-option of molecular mimicry as a strategy for achieving its function.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	49
Volume Number	290
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2015-12-04
Publisher Place	United States
Access Restriction	Open
Subject Keyword	FMN Reductase Genetics Mitochondrial Membrane Transport Proteins Chemistry Mutation Vitamin B 12 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase Metabolism Amino Acid Motifs Amino Acid Sequence Crystallography, X-Ray Cytoplasm Homocystinuria Ligands Lysosomes Molecular Mimicry Molecular Sequence Data Mutation, Missense Oxygen Protein Conformation Protein Folding Protein Structure, Secondary Protein Transport Sequence Homology, Amino Acid X-Ray Diffraction Research Support, N.I.H., Extramural Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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