MeaB is an accessory GTPase protein involved in the assembly, protection and reactivation of 5'-deoxyadenosylcobalamin-dependent methyl malonyl-CoA mutase (MCM). Mutations in the human ortholog of MeaB result in methylmalonic aciduria, an inborn error of metabolism. G-proteins typically utilize conserved switch I and II motifs for signaling to effector proteins via conformational changes elicited by nucleotide-binding and hydrolysis. Our recent discovery that MeaB employs an unusual switch III region for bidirectional signaling with MCM raised questions about the roles of the switch I and II motifs in MeaB. In this study, we have addressed the functions of conserved switch II residues by performing alanine-scanning mutagenesis. Our results demonstrate that the GTPase activity of MeaB is auto-inhibited by switch II and that this loop is important for coupling nucleotide-sensitive conformational changes in switch III to elicit the multiple chaperone functions of MeaB. Furthermore, we report the structure of MeaB-GDP crystallized in the presence of AlFx- in order to form the putative transition state analog, GDP-AlF4-. The resulting crystal structure and its comparison to related G-proteins supports the conclusion that the catalytic site of MeaB is incomplete in the absence of the GTPase-activating protein, MCM, and therefore unable to stabilize the transition state analog. Favoring an inactive conformation in the absence of the client MCM protein might represent a strategy for suppressing the intrinsic GTPase activity of MeaB in which the switch II loop plays an important role.