5CUZ

Crystal structure of SeMet-substituted N-terminal truncated human B12-chaperone CblD (108-296)

Summary for 5CUZ

• Entry DOI: 10.2210/pdb5cuz/pdb
• Related: 5CV0
• Descriptor: Methylmalonic aciduria and homocystinuria type D protein, mitochondrial (2 entities in total)
• Functional Keywords: vitamin b12, nitro-fmn-reductase, chaperone
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9H3L0
• Total number of polymer chains: 1
• Total formula weight: 22074.98

Authors

Yamada, K.,Gherasim, C.,Banerjee, R.,Koutmos, M. (deposition date: 2015-07-25, release date: 2015-09-23, Last modification date: 2024-10-23)

Primary citation

Yamada, K.,Gherasim, C.,Banerjee, R.,Koutmos, M.
Structure of Human B12 Trafficking Protein CblD Reveals Molecular Mimicry and Identifies a New Subfamily of Nitro-FMN Reductases.
J.Biol.Chem., 290:29155-29166, 2015

PubMed 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 α+β 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.

PubMed: 26364851
DOI: 10.1074/jbc.M115.682435

Experimental method

X-RAY DIFFRACTION (2.31 Å)