title: A switch III motif relays signaling between a B12 enzyme and its G-protein chaperone.
abstract: Fidelity during cofactor assembly is essential for the proper functioning of metalloenzymes and is ensured by specific chaperones. MeaB, a G-protein chaperone for the coenzyme B12-dependent radical enzyme methylmalonyl-CoA mutase (MCM), uses the energy of GTP binding, hydrolysis or both to regulate cofactor loading into MCM, protect MCM from inactivation and rescue MCM that is inactivated during turnover. Typically, G proteins signal to client proteins using the conformationally mobile switch I and II loops. Crystallographic snapshots of MeaB reported herein reveal a new switch III element that has substantial conformational plasticity. Using alanine-scanning mutagenesis, we demonstrate that the switch III motif is critical for bidirectional signal transmission of the GTPase-activating protein activity of MCM and the chaperone functions of MeaB in the MeaB-MCM complex. Mutations in the switch III loop identified in patients corrupt this interprotein communication and lead to methylmalonic aciduria, an inborn error of metabolism.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Lofgren
authors.forename: Dominique
authors.initials: D
authors.lastname: Padovani
authors.forename: Markos
authors.initials: M
authors.lastname: Koutmos
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D020816:Amino Acid Motifs; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008765:Methylmalonyl-CoA Mutase / Q000737:chemistry / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D015398:Signal Transduction; D014805:Vitamin B 12 / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D019204:GTP-Binding Proteins; D008765:Methylmalonyl-CoA Mutase; D014805:Vitamin B 12