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2.A.127 The Enterobacterial Cardiolipin Transporter (CLT) Family 

During infection, Gram-negative bacteria remodel their OM to promote survival and replication within host tissues. Salmonella rely on the PhoPQ two-component regulators to coordinate OM remodeling in response to environmental cues. In a screen for mediators of PhoPQ-regulated OM remodeling in Salmonella enterica Typhimurium, Dalebroux et al. 2015 identified PbgA (formerly YejM with a DUF3413 transmembrane domain (N-terminus) and a periplasmic alkaline phosphatase (ALP-like) domain (C-terminus)).  The latter binds cardiolipin glycerophospholipids (CL) near the inner membrane and promotes their PhoPQ-regulated trafficking to the OM. Purified-PbgA oligomers are tetrameric, and the periplasmic domain contains a globular region that binds to the OM in a PhoPQ-dependent manner. Thus, PbgA forms a complex that may bridge the envelope for regulated cardiolipin delivery.  PbgA globular region-deleted mutant bacteria are severely attenuated for pathogenesis, suggesting that increased cardiolipin trafficking to the OM is necessary for Salmonella to survive within host tissues that activate PhoPQ.

The outer membrane of Gram-negative bacteria is asymmetric with the outer leaflet being composed of lipopolysaccharide (LPS) and the inner leaflet is formed by glycerophospholipid (GPL). Cardiolipin (CL) plays an important role in OM biogenesis and pathogenesis, and the inner membrane (IM) protein PbgA, containing five N-terminal TMSs and a globular CL-binding domain in the periplasm. Two crystal structures of the C-terminal soluble periplasmic globular domains of PbgA from S. typhimurium and E. coli have been solved, which revealed that the globular domains of PbgA resemble the structures of the arylsulfatase protein family and contains a novel core hydrophobic pocket that may be responsible for binding and transporting CLs (Dong et al. 2016).

The CLT family is annotated in Pfam/CDD as the YejM, ALP and As1P membrane anchored periplasmic protein YejM alkaline phosphatase/cell wall sulfatase family. Sulfatases catalyze the hydrolysis of sulfate esters from wide range of substrates including steroids, carbohydrates and proteins. Sulfate esters may be formed from various alcohols and amines. The biological roles of sulfatase include the cycling of sulfur in the environment, the degradation of sulfated glycosaminoglycans and glycolipids (in the lysosomes of eukaryotes), and in remodeling sulfated glycosaminoglycans in the extracellular space. Sulfatases are essential for human metabolism. At least eight human monogenic diseases are caused by the deficiency of individual sulfatases.

Strain LH530, a mutant of Escherichia coli K-12, was reported by others to show increased outer membrane permeability, temperature-sensitive growth, and reduced synthesis of lipid A. The  mutant gene is suppressed by high-copy-number plasmids carrying the wild-type acpT gene, which encodes a protein that catalyzes the attachment of 4'-phosphopantetheine. De Lay and Cronan 2008 mapped the mutation to yejM. Deletion of the entire yejM gene was lethal. Suppression by AcpT overexpression was specific to AcpT snf did not require that AcpT be enzymatically active.

The generalized transport reaction catalyzed by PbgA is:

CL (inner membrane) → CL (outer membrane).

References associated with 2.A.127 family:

Dalebroux, Z.D., M.B. Edrozo, R.A. Pfuetzner, S. Ressl, B.R. Kulasekara, M.P. Blanc, and S.I. Miller. (2015). Delivery of cardiolipins to the Salmonella outer membrane is necessary for survival within host tissues and virulence. Cell Host Microbe 17: 441-451. 25856753
Dong, H., Z. Zhang, X. Tang, S. Huang, H. Li, B. Peng, and C. Dong. (2016). Structural insights into cardiolipin transfer from the Inner membrane to the outer membrane by PbgA in Gram-negative bacteria. Sci Rep 6: 30815. 27487745
Fan, J., E.M. Petersen, T.R. Hinds, N. Zheng, and S.I. Miller. (2020). Structure of an Inner Membrane Protein Required for PhoPQ-Regulated Increases in Outer Membrane Cardiolipin. mBio 11:. 32047135