Chaperonins are macromolecular machines that assist in protein folding. The 
archaeon Methanosarcina mazei has acquired numerous bacterial genes by 
horizontal gene transfer. As a result, both the bacterial group I chaperonin, 
GroEL, and the archaeal group II chaperonin, thermosome, coexist. A 
proteome-wide analysis of chaperonin interactors was performed to determine the 
differential substrate specificity of GroEL and thermosome. At least 13% of 
soluble M. mazei proteins interact with chaperonins, with the two systems having 
partially overlapping substrate sets. Remarkably, chaperonin selectivity is 
independent of phylogenetic origin and is determined by distinct structural and 
biochemical features of proteins. GroEL prefers well-conserved proteins with 
complex alpha/beta domains. In contrast, thermosome substrates comprise a group 
of faster-evolving proteins and contain a much wider range of different domain 
folds, including small all-alpha and all-beta modules, and a greater number of 
large multidomain proteins. Thus, the group II chaperonins may have facilitated 
the evolution of the highly complex proteomes characteristic of eukaryotic 
cells.