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Function

FhaC membrane transporter is a protein in the Omp85 family. It involves two polypeptide-transport associated (POTRA) domains, which are involved in substrate recognition. This protein's main function is to aid in FHA, or filamentous hemagglutinin, secretion. This is carried out by a two-partner secretion system, where FhaC is the translocase and FHA is the substrate. The beta-barrel conformation provides the pore for FHA transport through the membrane of the cell. The substrate is involved in a competitive mechanism with a linker protein, H1 helix, that normally rests inside of the barrel to block transport. This helix interacts weakly with the POTRA2 domain, to sit inside the pore. When the substrate (FHA) arrives at the transport site, it competes with the linker protein for the interaction with the POTRA2 domain. This pushes the H1 helix out, allowing the pore to be used for FHA secretion. ^[1]

Disease

FhaC and FHA is a system that is found and is responsible for virulence in Bordetella pertussis. Bordetella pertussis is a bacteria that is the main cause of pertussis, or whooping cough, in humans. This is an infection that is especially dangerous for young infants and the elderly. FHA, secreted through the FhaC protein, is essential for establishing infection in the lower respiratory tract in pertussis. It accomplishes this by mediating adherence to respiratory epithelia, or the “skin cells” in the respiratory tract. FHA also plays an important role in suppressing the initial inflammatory response to infection, promoting bacterial persistence. ^[2]

Relevance

FhaC and FHA are one of the most studied two-partner secretion systems. This secretion system is used in gram-negative bacteria and contributes to pathogenicity in these bacteria. FhaC is, in particular, involved in virulence and formation of biofilm in the gram-negative bacteria Bordetella pertussis. It is important to know the structure and function of this specific membrane transporter, because if the mechanism of virulence is known, the possibility of using this site as a target for fighting infections is increased.

Structural highlights

The structure of this protein is a wide, round barrel shape, with two POTRA domains just below the barrel, and a linker protein at the N-terminus, the H1 helix. An important feature of this protein’s structure is the “lid-lock” formation with the interaction of two signature motifs, one in the inner barrel wall, and one at the tip of the L6 loop. The acts as a plug for the membrane transporter by traversing the entire length of the barrel, sitting inside the pore, blocking activity through the pore. This happens in the absence of substrates, so in these conditions, the barrel is “inactive.” H1 can be displaced by substrate binding. When displaced, the H1 helix rests flexibly on the periplasmic face membrane near the two POTRA domains. The is required for channel stability and FHA secretion. The motif in the L6 loop interacts with the motif on the inner wall through close spatial contact and through salt bridges. This ensures the lid-lock formation that is necessary for stability and aids in FHA secretion through the insertion site which is also on the L6 loop.