A Pseudokinase Debut at the Mycobacterial Cell Wall

Digby F. Warner^* and Valerie Mizrahi^*

MRC/NHLS/UCT Molecular Mycobacteriology Research Unit and DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Institute of Infectious Disease and Molecular Medicine, and Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Private Bag X3, Rondebosch 7701, Cape Town, South Africa.

Abstract: Mycobacterium tuberculosis, the causative agent of tuberculosis, has a complex cellular envelope that comprises both the cytoplasmic membrane and the outer cell wall. Despite advances in elucidating the structural and biochemical composition of these features, the processes that ensure cell wall homeostasis remain poorly understood. New findings implicate the essential mycobacterial serine-threonine protein kinase (STPK), PknB, in regulating the formation of a regulatory complex that includes the integral membrane protein MviN, which is required for peptidoglycan biosynthesis, and a forkhead-associated (FHA) domain protein, FhaA. A model has emerged in which a peptidoglycan-derived muropeptide signal triggers the PknB-mediated phosphorylation of the MviN pseudokinase domain, which in turn recruits the FHA-containing regulatory protein to inhibit peptidoglycan biosynthesis at the cell poles and septum. In establishing PknB as central regulator of this pathway, the model reinforces the major role of this STPK network in the orchestration of fundamental mycobacterial processes, and, with the identification of MviN as having a catalytically inactive and highly divergent kinase homology domain, the model establishes a pseudokinase as a key player in cell wall metabolism.

* Corresponding authors. E-mail: digby.warner{at}uct.ac.za (D.F.W.); valerie.mizrahi{at}uct.ac.za (V.M.)

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