Molecular insights into how the motions of the β-barrel and POTRA domains of BamA are coupled for efficient function

Naemi Csoma, Jonathan M. Machin, James M. Whitehouse, Raquel Rodrìguez-Alonso, Monika Olejnik, Adam K. Cahill, Seung-Hyun Cho, Till F. Schäberle, Bogdan I. Iorga, Neil A. Ranson, Sheena E. Radford (), Antonio N. Calabrese () and Jean-François Collet ()
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Naemi Csoma: WEL Research Institute
Jonathan M. Machin: University of Leeds
James M. Whitehouse: University of Leeds
Raquel Rodrìguez-Alonso: WEL Research Institute
Monika Olejnik: University of Leeds
Adam K. Cahill: University of Leeds
Seung-Hyun Cho: WEL Research Institute
Till F. Schäberle: Justus-Liebig-University Giessen
Bogdan I. Iorga: Université catholique de Louvain (UCLouvain)
Neil A. Ranson: University of Leeds
Sheena E. Radford: University of Leeds
Antonio N. Calabrese: University of Leeds
Jean-François Collet: WEL Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The β-barrel assembly machinery (BAM) inserts β-barrel proteins into the outer membrane of Gram-negative bacteria, forming an essential permeability barrier. The core BAM component, BamA, is a β-barrel protein with an N-terminal periplasmic extension comprising five polypeptide transport-associated (POTRA) domains. Whilst BamA’s structure is well characterised, it remains unclear how β-barrel and POTRA domain motions are coordinated. Using BamA variants with mutations in the hinge region between these two domains, we demonstrate that hinge flexibility is required for BAM function. Cryo-electron microscopy suggests that hinge rigidity impairs function by structurally decoupling these domains. A screen for spontaneous suppressors identified a mutation at position T434 in an extracellular loop of BamA, which has been previously shown to suppress BAM defects. Studying this variant provides insights into its function as a general rescue mechanism. Our findings underscore how BamA’s sequence has been evolutionarily optimised for efficient function.

Date: 2025
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DOI: 10.1038/s41467-025-63897-y

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