Allosteric Regulation of Oligomerization by a B12 Trafficking G-Protein Is Corrupted in Methylmalonic Aciduria.

Affiliation

Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA. Electronic address: [Email]

Abstract

Allosteric regulation of methylmalonyl-CoA mutase (MCM) by the G-protein chaperone CblA is transduced via three "switch" elements that gate the movement of the B12 cofactor to and from MCM. Mutations in CblA and MCM cause hereditary methylmalonic aciduria. Unlike the bacterial orthologs used previously to model disease-causing mutations, human MCM and CblA exhibit a complex pattern of regulation that involves interconverting oligomers, which are differentially sensitive to the presence of GTP versus GDP. Patient mutations in the switch III region of CblA perturb the nucleotide-sensitive distribution of the oligomeric complexes with MCM, leading to loss of regulated movement of B12 to and/or from MCM and explain the molecular mechanism of the resulting disease.

Keywords

G-protein,GTPase,MMAA,cblA,cobalamin,cofactor,metal trafficking,metalloprotein,trafficking,vitamin B(12),

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