5UJC

Crystal structure of a C.elegans B12-trafficking protein CblC, a human MMACHC homologue

Summary for 5UJC

• Entry DOI: 10.2210/pdb5ujc/pdb
• Descriptor: MMACHC-like protein, CO-METHYLCOBALAMIN, L(+)-TARTARIC ACID, ... (6 entities in total)
• Functional Keywords: vitamin b12, oxidoreductase, b12 trafficking, b12 processing, b12 binding
• Biological source: Caenorhabditis elegans
• Cellular location: Cytoplasm : Q7Z144
• Total number of polymer chains: 1
• Total formula weight: 33238.43

Authors

Li, Z.,Shanmuganathan, A.,Ruetz, M.,Yamada, K.,Lesniak, N.A.,Krautler, B.,Brunold, T.C.,Banerjee, R.,Koutmos, M. (deposition date: 2017-01-17, release date: 2017-05-03, Last modification date: 2023-10-04)

Primary citation

Li, Z.,Shanmuganathan, A.,Ruetz, M.,Yamada, K.,Lesniak, N.A.,Krautler, B.,Brunold, T.C.,Koutmos, M.,Banerjee, R.
Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC.
J. Biol. Chem., 292:9733-9744, 2017

PubMed Abstract: The cobalamin or B cofactor supports sulfur and one-carbon metabolism and the catabolism of odd-chain fatty acids, branched-chain amino acids, and cholesterol. CblC is a B-processing enzyme involved in an early cytoplasmic step in the cofactor-trafficking pathway. It catalyzes the glutathione (GSH)-dependent dealkylation of alkylcobalamins and the reductive decyanation of cyanocobalamin. CblC from (CblC) also exhibits a robust thiol oxidase activity, converting reduced GSH to oxidized GSSG with concomitant scrubbing of ambient dissolved O The mechanism of thiol oxidation catalyzed by CblC is not known. In this study, we demonstrate that novel coordination chemistry accessible to CblC-bound cobalamin supports its thiol oxidase activity via a glutathionyl-cobalamin intermediate. Deglutathionylation of glutathionyl-cobalamin by a second molecule of GSH yields GSSG. The crystal structure of CblC provides insights into how architectural differences at the α- and β-faces of cobalamin promote the thiol oxidase activity of CblC but mute it in wild-type human CblC. The R161G and R161Q mutations in human CblC unmask its latent thiol oxidase activity and are correlated with increased cellular oxidative stress disease. In summary, we have uncovered key architectural features in the cobalamin-binding pocket that support unusual cob(II)alamin coordination chemistry and enable the thiol oxidase activity of CblC.

PubMed: 28442570
DOI: 10.1074/jbc.M117.788554

Experimental method

X-RAY DIFFRACTION (1.35 Å)