A reappraisal of mycobacterial chaperonin 60 structure and function and its role in tuberculosis. (360G-Wellcome-081315_B_06_Z)

The study of the highly conserved and essential E. coli chaperonin 60 (GroEL) has been instrumental in the establishment of a new paradigm for the cellular control of protein folding. In the last decade this protein and some of its homologues have also been found to induce activation of myeloid cells, suggesting it can act as a 'danger signal' in immunity. Recent structural and functional studies of the two chaperonin 60 (Cpn60) proteins of the major human pathogen Mycobacterium tuberculosis have revealed major differences to E. coli GroEL in oligomeric structure, protein folding function and intercellular signalling activity. Neither of the two M. tuberculosis Cpn60 proteins form the typical "double ring" form of E. coli GroEL under standard conditions, but we have found that both are able to complement at least partially for loss of the essential E. coli groEL gene. We have also recently found that that the cpn60.1 gene of M. tuberculosis can be deleted without a significant effect on bacterial growth, but that organisms lacking this gene fail to induce chronic granulomatous lung inflammation in both mice and guinea pigs. This proposal is to investigate the highly atypical structure and function of the Mycobacterial chaperonins in more detail, and, in particular, to test the hypothesis that there is a link between their atypical structures and their roles in infection, cell signalling, and bacterial growth.