The crystal structure of the Mycobacterium tuberculosis Rv3019c-Rv3020c ESX complex reveals a domain-swapped heterotetramer.
Mycobacterium tuberculosis encodes five gene clusters (ESX-1 to ESX-5) for Type VII protein secretion systems that are implicated in mycobacterial pathogenicity. Substrates for the secretion apparatus are encoded within the gene clusters and in additional loci that lack the components of the secretion apparatus. The best characterized substrates are the ESX complexes, 1:1 heterodimers of ESAT-6 and CFP-10, the prototypical member that has been shown to be essential for Mycobacterium tuberculosis pathogenesis. We have determined the structure of EsxRS, a homolog of EsxGH of the ESX-3 gene cluster, at 1.91 Å resolution. The EsxRS structure is composed of two four-helix bundles resulting from the 3D domain swapping of the C-terminal domain of EsxS, the CFP-10 homolog. The four-helix bundles at the extremities of the complex have a similar architecture to the structure of ESAT-6·CFP-10 (EsxAB) of ESX-1, but in EsxRS a hinge loop linking the α-helical domains of EsxS undergoes a loop-to-helix transition that creates the domain swapped EsxRS tetramer. Based on the atomic structure of EsxRS and existing biochemical data on ESX complexes, we propose that higher order ESX oligomers may increase avidity of ESX binding to host receptor molecules or, alternatively, the conformational change that creates the domain swapped structure may be the basis of ESX complex dissociation that would free ESAT-6 to exert a cytotoxic effect.
Arbing
Mark A
MA
UCLA-DOE Institute for Genomics and Proteomics, UCLA, Los Angeles, California 90095-1570, USA.
Kaufmann
Markus
M
Phan
Tung
T
Chan
Sum
S
Cascio
Duilio
D
Eisenberg
David
D
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D005810:Multigene Family; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000235:genetics; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D001426:Bacterial Proteins