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

Journal Article · Wed Apr 01 00:00:00 EDT 2015 · Cell

DOI:https://doi.org/10.1016/j.cell.2015.03.040· OSTI ID:1392135

Rosenberg, Oren S.; Dovala, Dustin; Li, Xueming; Connolly, Lynn; Bendebury, Anastasia; Finer-Moore, Janet; Holton, James; Cheng, Yifan; Stroud, Robert M.; Cox, Jeffery S.

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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: AC02-06CH11357; AC02-05CH11231; P41GM103393
• OSTI ID: 1392135
• Alternate ID(s): OSTI ID: 1178832
• Journal Information: Cell, Journal Name: Cell Vol. 161 Journal Issue: 3; ISSN 0092-8674
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES