Domain Orientation in the Inactive Response Regulator Mycobacterium tuberculosis MtrA Provides a Barrier to Activation
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- 作者：Natalia Friedland ; Timothy R. Mack ; Minmin Yu ; Li-Wei Hung ; Thomas C. Terwilliger ; Geoffrey S. Waldo ; Ann M. Stock
- 刊名：Biochemistry
- 出版年：2007
- 出版时间：June 12, 2007
- 年：2007
- 卷：46
- 期：23
- 页码：6733 - 6743
- 全文大小：432K
- 年卷期：v.46,no.23(June 12, 2007)
- ISSN：1520-4995
文摘
The structure of MtrA, an essential gene product for the human pathogen Mycobacteriumtuberculosis, has been solved to a resolution of 2.1 Å. MtrA is a member of the OmpR/PhoB family ofresponse regulators and represents the fourth family member for which a structure of the protein in itsinactive state has been determined. As is true for all OmpR/PhoB family members, MtrA possesses anN-terminal regulatory domain and a C-terminal winged helix-turn-helix DNA-binding domain, withphosphorylation of the regulatory domain modulating the activity of the protein. In the inactive form ofMtrA, these two domains form an extensive interface that is composed of the 
4-
5-5 face of theregulatory domain and the C-terminal end of the positioning helix, the trans-activation loop, and therecognition helix of the DNA-binding domain. This domain orientation suggests a mechanism of mutualinhibition by the two domains. Activation of MtrA would require a disruption of this interface to allowthe 4-5-5 face of the regulatory domain to form the intermolecule interactions that are associatedwith the active state and to allow the recognition helix to interact with DNA. Furthermore, the interfaceappears to stabilize the inactive conformation of MtrA, potentially reducing the rate of phosphorylationof the N-terminal domain. This combination of effects may form a switch, regulating the activity of MtrA.The domain orientation exhibited by MtrA also provides a rationale for the variation in linker length thatis observed within the OmpR/PhoB family of response regulators.
4-5-5 face of theregulatory domain and the C-terminal end of the positioning helix, the trans-activation loop, and therecognition helix of the DNA-binding domain. This domain orientation suggests a mechanism of mutualinhibition by the two domains. Activation of MtrA would require a disruption of this interface to allowthe 4-5-5 face of the regulatory domain to form the intermolecule interactions that are associatedwith the active state and to allow the recognition helix to interact with DNA. Furthermore, the interfaceappears to stabilize the inactive conformation of MtrA, potentially reducing the rate of phosphorylationof the N-terminal domain. This combination of effects may form a switch, regulating the activity of MtrA.The domain orientation exhibited by MtrA also provides a rationale for the variation in linker length thatis observed within the OmpR/PhoB family of response regulators.