Mutations in the PCCA or PCCB genes coding for alpha and beta subunits of 
propionyl CoA carboxylase can cause propionic acidemia. To understand the 
molecular basis of the intragenic complementation previously reported at the 
PCCB locus, we now examine the complementation behaviour of four 
carboxy-terminal and 11 amino-terminal naturally occurring mutant alleles both 
using cell fusion and reconstructing the complementation event by transfecting 
the mutant cDNAs to generate multimeric hybrid proteins. Alleles carrying 
mutations p.R410W and p.W531X are able to complement with 10 out of 11 
amino-terminal mutations assayed. Only the unstable p.R512C, p.L519P and p.G112D 
mutants fail to complement. The results analyzed in the framework of the crystal 
structure of the homologous 12S transcarboxylase from Propionibacterium 
shermanii show that all mutant alleles studied are located at beta subunits 
interfaces, complementing alleles at the inter-trimer interface, where the 
catalysis probably happens, and non-complementing alleles at the intra-trimer 
interface, probably disrupting the trimer formation. Our results also show a 
remarkable stabilization effect when p.R410W is cotransfected with p.G246V. We 
propose a model for intragenic complementation requiring the production of two 
different beta subunits carrying carboxy and amino-terminal mutations that allow 
regenerating functional active sites and in which a stabilization effect between 
subunits could be relevant to ameliorate the biochemical phenotype of each 
mutation separately.