5cuz
Crystal structure of SeMet-substituted N-terminal truncated human B12-chaperone CblD (108-296)
Structural highlights
DiseaseMMAD_HUMAN Methylcobalamin deficiency type cblDv1;Methylmalonic acidemia with homocystinuria, type cblD;Vitamin B12-responsive methylmalonic acidemia, type cblDv2. The disease is caused by mutations affecting the gene represented in this entry. FunctionMMAD_HUMAN Involved in cobalamin metabolism.[1] Publication Abstract from PubMedIn 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. The methylmalonic aciduria and homocystinuria type D protein (MMADHC) 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 the methylmalonic aciduria and homocystinuria type C protein (MMADHC) or CblC and for supporting the cytoplasmic cobalamin trafficking pathway. CblD contains an alpha+beta 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. Structure of Human B12 trafficking protein CblD reveals molecular mimicry and identifies a new subfamily of Nitro-FMN reductases.,Yamada K, Gherasim C, Banerjee R, Koutmos M J Biol Chem. 2015 Sep 13. pii: jbc.M115.682435. PMID:26364851[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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