Crystal Structure And Mutagenisis of the Metallochaperone MeaB: Insight Into the Causes of the Methylmalonic Aciduria

Journal Article · Mon Jun 01 04:00:00 EDT 2009 · J. Biol. Chem. 282:31308,2007

OSTI ID:953995

Hubbard, P A; Padovani, D; Labunska, T; Mahlstedt, S A; Banerjee, R; Drennan, C L

MeaB is an auxiliary protein that plays a crucial role in the protection and assembly of the B{sub 12}-dependent enzyme methylmalonyl-CoA mutase. Impairments in the human homologue of MeaB, MMAA, lead to methylmalonic aciduria, an inborn error of metabolism. To explore the role of this metallochaperone, its structure was solved in the nucleotide-free form, as well as in the presence of product, GDP. MeaB is a homodimer, with each subunit containing a central {alpha}/{beta}-core G domain that is typical of the GTPase family, as well as a-helical extensions at the N and C termini that are not found in other metalloenzyme chaperone GTPases. The C-terminal extension appears to be essential for nucleotide-independent dimerization, and the N-terminal region is implicated in protein-protein interaction with its partner protein, methylmalonyl-CoA mutase. The structure of MeaB confirms that it is a member of the G3E family of P-loop GTPases, which contains other putative metallochaperones HypB, CooC, and UreG. Interestingly, the so-called switch regions, responsible for signal transduction following GTP hydrolysis, are found at the dimer interface of MeaB instead of being positioned at the surface of the protein where its partner protein methylmalonyl-CoA mutase should bind. This observation suggests a large conformation change of MeaB must occur between the GDP- and GTP-bound forms of this protein. Because of their high sequence homology, the missense mutations in MMAA that result in methylmalonic aciduria have been mapped onto MeaB and, in conjunction with mutagenesis data, provide possible explanations for the pathology of this disease.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 953995
• Report Number(s): SLAC-REPRINT-2009-397
• Journal Information: J. Biol. Chem. 282:31308,2007, Journal Name: J. Biol. Chem. 282:31308,2007 Journal Issue: 43 Vol. 282; ISSN JBCHA3; ISSN 0021-9258
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CRYSTAL STRUCTURE
DIMERIZATION
DIMERS
ENZYMES
ERRORS
HUMAN POPULATIONS
HYDROLYSIS
INTERACTIONS
INTERFACES
METABOLISM
MUTAGENESIS
MUTATIONS
Other
OTHER
BIO
CHEM
PATHOLOGY
PROTEINS
RECEPTORS
SAFETY
SIGNALS
SURFACES
VITAMIN B-12