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

We report that 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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [5] ;  [6] ;  [5] ;  [5] ;  [2]
  1. Univ. of California, San Francisco, CA (United States). Division of Infectious Diseases
  2. Univ. of California, San Francisco, CA (United States). Dept. of Microbiology and Immunology
  3. Tsinghua Univ., Beijing (China)
  4. Univ. of California, San Francisco, CA (United States). Division of Infectious Diseases; Achaogen Inc., South San Francisco, CA (United States)
  5. Univ. of California, San Francisco, CA (United States). Dept. of Biophysics and Biochemistry
  6. Univ. of California, San Francisco, CA (United States). Dept. of Biophysics and Biochemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
OSTI Identifier:
1178832
Grant/Contract Number:
AC02-06CH11357; AC02-05CH11231; P41GM103393
Type:
Accepted Manuscript
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 161; Journal Issue: 3
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES