Format

Send to

Choose Destination
Cell. 2015 Apr 23;161(3):501-512. doi: 10.1016/j.cell.2015.03.040. Epub 2015 Apr 9.

Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion.

Author information

1
Division of Infectious Diseases, Department of Medicine, UCSF Medical Center, University of California, San Francisco, San Francisco, CA 94143-0654, USA.
2
Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA.
3
School of Life Sciences, Tsinghua University, Beijing 100084, China.
4
Division of Infectious Diseases, Department of Medicine, UCSF Medical Center, University of California, San Francisco, San Francisco, CA 94143-0654, USA; Achaogen, Inc., South San Francisco, CA 94080, USA.
5
Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Lawrence Berkeley National Laboratory, MS6-2100, Berkeley, CA 94720, USA.
7
Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jeffery.cox@ucsf.edu.

Abstract

Mycobacterium tuberculosis and Staphylococcus aureus secrete virulence factors via type VII protein secretion (T7S), a system that intriguingly requires all of its secretion substrates for activity. To gain insights into T7S function, we used structural approaches to guide studies of the putative translocase EccC, a unique enzyme with three ATPase domains, and its secretion substrate EsxB. The crystal structure of EccC revealed that the ATPase domains are joined by linker/pocket interactions that modulate its enzymatic activity. EsxB binds via its signal sequence to an empty pocket on the C-terminal ATPase domain, which is accompanied by an increase in ATPase activity. Surprisingly, substrate binding does not activate EccC allosterically but, rather, by stimulating its multimerization. Thus, the EsxB substrate is also an integral T7S component, illuminating a mechanism that helps to explain interdependence of substrates, and suggests a model in which binding of substrates modulates their coordinate release from the bacterium.

PMID:
25865481
PMCID:
PMC4409929
DOI:
10.1016/j.cell.2015.03.040
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center