Mycobacterial outer membranes: in search of proteins

Abstract

The cell wall is a major virulence factor of Mycobacterium tuberculosis and contributes to its intrinsic drug resistance. Recently, cryo-electron microscopy showed that mycobacterial cell wall lipids form an unusual outer membrane. Identification of the components of the uptake and secretion machinery across this membrane will be crucial for understanding the physiology and pathogenicity of M. tuberculosis and for the development of better anti-tuberculosis drugs. Although the genome of M. tuberculosis appears to encode over 100 putative outer membrane proteins, only a few have been identified and characterized. Here, we summarize the current knowledge on the structure of the mycobacterial outer membrane and its known proteins. Through comparison to transport processes in Gram-negative bacteria, we highlight several hypothetical outer membrane proteins of M. tuberculosis that await discovery.

Figure 1

Cryo-electron microscopy of the mycobacterial cell envelope. The mycobacterial outer membrane (MOM) from Mycobacterium bovis BCG is visualized by cryosectioning (a) and by cryo-electron tomography (b). The periplasmic space between the MOM and the cytoplasmic membrane (CM) contains the layers of the arabinogalactan-peptidoglycan polymer (indicated in blue in the 3-D representation). Scale bars: 50 nm. Adapted, with permission, from Ref. [18].

Figure 2

Models of the mycobacterial outer membrane and cell envelope. (a) Schematic structure of mycolic acids in the elongated and folded conformation (based on the major components found in M. tuberculosis [24, 103]). (b) Models of the mycobacterial outer membrane (adapted, with permission, from Refs. [18, 19]). Mycolic acids are drawn in red and inserted either in the elongated conformation (model I, left side) or the folded conformation (model II, right side). A porin, here MspA from M. smegmatis, is represented in blue. The symbols of lipid head groups indicate that different free lipids may occur in both leaflets of the outer membrane. Scale bar: 10 nm. (c) Model of the mycobacterial cell envelope. The dimensions of the membranes and the periplasmic layers are taken from [18]. Abbreviations: CM, cytoplasmic membrane (membrane proteins are not shown); L1 and L2, periplasmic layers of still unknown identity (L2 represents at least part of the peptidoglycan-arabinogalactan polymer); MOM, mycobacterial outer membrane according to the representation in (b). The hydrophobic matrix of membranes is indicated in yellow color. The models in (b) and (c) are approximately drawn to scale.

Figure 3

Structure of the porin MspA of M. smegmatis. (a) Side view, (b) top view. The atomic coordinates of MspA were taken from the crystal structure (PDB accession code: 1UUN [10]). Alternating adjacent monomers are colored in red and blue.