Chapter 8 : Outer Membrane Protein Insertion by the β-barrel Assembly Machine

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The presence in Gram-negative bacteria of an extracytoplasmic outer membrane (OM), which is distinct from the inner membrane (IM) both in constitution and in function, presents a complex topological problem, as all proteinaceous and lipidic OM components are synthesized cytoplasmically ( ). In order to reach their destination in the growing OM, these components must translocate across the IM and traverse the aqueous, crowded periplasmic space. This problem is solved through a series of semi-independent and highly conserved transport pathways that coordinate the efficient delivery and integration of all OM constituents.

Citation: Ricci D, Silhavy T. 2019. Outer Membrane Protein Insertion by the β-barrel Assembly Machine, p 91-101. In Sandkvist M, Cascales E, Christie P (ed), Protein Secretion in Bacteria. ASM Press, Washington, DC. doi: 10.1128/ecosalplus.ESP-0035-2018
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Figure 1

(a) The BamA β-barrel (pink) is asymmetric, with one face forming a narrow protein-lipid interface (approximated by the dashed line) that is thought to physically alter the local properties of the bilayer (green). (b) The activated BamA β-barrel undergoes a dramatic conformational rearrangement that disrupts the continuous β-barrel structure, separates the β-strands comprising the lateral gate (β1 and β16), and exposes an aqueous channel that spans the membrane. Additionally, a highly conserved extracellular loop (L6, blue) internally braces and globally stabilizes the β-barrel domain and compensates for the instability introduced by the conformational dynamics. This image was generated using PDB structures 4K3B (left) and 5EKQ (right).

Citation: Ricci D, Silhavy T. 2019. Outer Membrane Protein Insertion by the β-barrel Assembly Machine, p 91-101. In Sandkvist M, Cascales E, Christie P (ed), Protein Secretion in Bacteria. ASM Press, Washington, DC. doi: 10.1128/ecosalplus.ESP-0035-2018
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Image of Figure 2
Figure 2

(a) A nascent eight-stranded OMP rapidly adsorbs to the surface (green) of the lipid bilayer, where hydrophobic lipid-facing side chains begin to penetrate into the membrane and β-strands assume a cloverleaf-like circular arrangement according to their relative position in the folded protein. (b) β-hairpins begin to form as the ends of the TM β-strands, oriented toward the center of the cloverleaf, plunge into the lipid phase. (c) Hydrogen bonds form between neighboring β-hairpins as they enter the membrane, stabilizing the native fold in concert with membrane insertion. The highlighted dashed line indicates the proposed path of the leading () ends of the β-strands.

Citation: Ricci D, Silhavy T. 2019. Outer Membrane Protein Insertion by the β-barrel Assembly Machine, p 91-101. In Sandkvist M, Cascales E, Christie P (ed), Protein Secretion in Bacteria. ASM Press, Washington, DC. doi: 10.1128/ecosalplus.ESP-0035-2018
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Figure 3

(a) Nascent OMPs (red), maintained in a folding-competent state by periplasmic chaperones (green), are transferred to the Bam complex (blue). (b) Client proteins associate with multiple epitopes on Bam, potentially stimulating formation of early β-structure and orienting circularly-arranged β-strands/hairpins toward the presumptive substrate exit pore. Recognition of conserved OMP motifs triggers a conformational change in BamA that exposes the barrel lumen and destabilizes the lateral gate, further perturbing the local membrane environment and generating an OM integration path for OMP substrates. (c) The Bam complex prevents aggregation, protects substrates from proteolysis, and lowers the kinetic barrier to OM integration to enable rapid OMP folding along the native pathway. (d) OMPs spontaneously fold into the locally destabilized membrane, with the exposed BamA lumen potentially accommodating the folding barrel and/or secreted extracellular domains of client proteins. (e) Release of substrate from the complex prompts restoration of the closed, inert state of the complex to enable an ensuing round of assembly.

Citation: Ricci D, Silhavy T. 2019. Outer Membrane Protein Insertion by the β-barrel Assembly Machine, p 91-101. In Sandkvist M, Cascales E, Christie P (ed), Protein Secretion in Bacteria. ASM Press, Washington, DC. doi: 10.1128/ecosalplus.ESP-0035-2018
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