Background: The ESX-1 type VII secretion system is an important determinant of virulence in pathogenic mycobacteria, including Mycobacterium tuberculosis. This complicated molecular machine secretes folded proteins through the mycobacterial cell envelope to subvert the host immune response. Despite its important role in disease very little is known about the molecular architecture of the ESX-1 secretion system.
Results: This study characterizes the structures of the soluble domains of two conserved core ESX-1 components – EccB1 and EccD1. The periplasmic domain of EccB1 consists of 4 repeat domains and a central domain, which together form a quasi 2-fold symmetrical structure. The repeat domains of EccB1 are structurally similar to a known peptidoglycan binding protein suggesting a role in anchoring the ESX-1 system within the periplasmic space. The cytoplasmic domain of EccD1has a ubiquitin-like fold and forms a dimer with a negatively charged groove.
Conclusions: These structures represent a major step towards resolving the molecular architecture of the entire ESX-1 assembly and may contribute to ESX-1 targeted tuberculosis intervention strategies.
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Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. Work performed in the laboratory of D.E. is supported by the Howard Hughes Medical Institute and National Institutes of Health grants 23616-002-06 F3:02, TBSGC P01 (AI068135), and TBSGC P01 (AI095208). Research reported in this publication was partially supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P20GM103486 and P30GM110787, and by the National Institute of Allergy and Infectious Diseases grant number R01AI119022 to KVK.
The structure factors and atomic coordinates have been deposited in the Protein Data Bank under accession codes 4KK7 (EccB1mt), 5CYU (EccB1ms), 4KV2 (cyto-EccD1mt), and 4KV3 (MBP-cyto-EccD1mt).
Wagner, Jonathan Mark; Chan, Sum; Evans, Timothy J.; Kahng, Sara; Kim, Jennifer; Arbing, Mark A.; Eisenberg, David; and Korotkov, Konstantin V., "Structures of EccB1 and EccD1 from the Core Complex of the Mycobacterial ESX-1 Type VII Secretion System" (2016). Molecular and Cellular Biochemistry Faculty Publication. 88.