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A switch III motif relays signaling between a B12 enzyme and its G-protein chaperone
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A switch III motif relays signaling between a B12 enzyme and its G-protein chaperone
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Journal Article
A switch III motif relays signaling between a B12 enzyme and its G-protein chaperone
2013
Overview
Heterotrimeric G proteins contain a switch III motif that regulates enzyme function. Structural and biochemical studies now identify a similar switch III loop in a nonheterotrimeric G-protein chaperone that explains the debilitating effects of mutations linked to methylmalonic aciduria.
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 B
12
-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.
Publisher
Nature Publishing Group US,Nature Publishing Group
