Abstract
The bacterial cytosol is a complex mixture of macromolecules (proteins, DNA, and RNA), which collectively are responsible for an enormous array of cellular tasks. Proteins are central to most, if not all, of these tasks and as such their maintenance (commonly referred to as protein homeostasis or proteostasis) is vital for cell survival during normal and stressful conditions. The two key aspects of protein homeostasis are, (i) the correct folding and assembly of proteins (coupled with their delivery to the correct cellular location) and (ii) the timely removal of unwanted or damaged proteins from the cell, which are performed by molecular chaperones and proteases, respectively. A major class of proteins that contribute to both of these tasks are the AAA+ (ATPases associated with a variety of cellular activities) protein superfamily. Although much is known about the structure of these machines and how they function in the model Gram-negative bacterium Escherichia coli, we are only just beginning to discover the molecular details of these machines and how they function in mycobacteria. Here we review the different AAA+ machines, that contribute to proteostasis in mycobacteria. Primarily we will focus on the recent advances in the structure and function of AAA+ proteases, the substrates they recognize and the cellular pathways they control. Finally, we will discuss the recent developments related to these machines as novel drug targets.
Highlights
In some cases these peptidases are activated for the energy-independent turnover of specific protein substrates, through the interaction with nonAAA+ components (Bai et al, 2016; Bolten et al, 2016)
Much is known about the structure of these machines and how they function in the model Gram-negative bacterium Escherichia coli, we are only just beginning to discover the molecular details of these machines and how they function in mycobacteria
The disease is caused by a single pathogen—Mycobacterium tuberculosis (Mtb) and the disease is eminently curable, the inappropriate administration of drugs has led to the emergence of several drug resistant strains, which are increasingly more difficult to eradicate
Summary
In some cases these peptidases are activated for the energy-independent turnover of specific protein substrates, through the interaction with nonAAA+ components (Bai et al, 2016; Bolten et al, 2016). In Msm, Lon is an 84 kDa protein composed of three domains, an N-terminal domain, which is generally required for substrate engagement, a central AAA+ domain and a C-terminal S16 peptidase domain (Figure 1).
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