A ‘molecular harpoon’ to protect bacteria

A study published in Nature Communications reveals a surprising mechanism by which bacteria activate a quality-control enzyme only when it is needed. This discovery could shed light on how other enzymes are regulated throughout the living world.

Gram-negative bacteria, such as Escherichia coli, have an outer membrane that protects them from their environment and acts as an effective barrier against many antibiotics. To function properly, this membrane must incorporate numerous proteins, the assembly of which is carried out by a molecular machinery known as BAM. However, when certain proteins do not fold correctly, they can disrupt this mechanism and compromise the integrity of the membrane.

To avoid these problems, bacteria have a specialised enzyme, called BepA, which is capable of removing defective proteins. However, one fundamental question remained unanswered: how does this potentially dangerous enzyme manage to activate only in the right place and at the right time, without destroying proteins that are in the process of being assembled?

In a study published in Nature Communications, researchers from the de Duve Institute (UCLouvain), in collaboration with teams from the Vrije Universiteit Brussel (VUB) and the VIB, have discovered a particularly ingenious mechanism.

By combining genetics, biochemistry and cryo-electron microscopy, scientists have shown that BepA possesses a flexible region that acts as a veritable ‘molecular harpoon’. When a defective protein blocks the BAM machinery, this harpoon unfolds and inserts itself into the outer membrane, enabling BepA to anchor itself there. This movement also promotes the release of a molecular lock that was keeping the enzyme inactive, thereby triggering its activity in the vicinity of the proteins to be broken down.

This discovery reveals a fascinating principle: the membrane is not merely a scaffold for proteins; it can also play a direct role in regulating their activity.

As well as being important for understanding how bacteria maintain their protective coating, this mechanism could also inspire research into other related enzymes, particularly those found in humans. It thus opens up new avenues of research into enzyme regulation and the fundamental mechanisms of protein quality control.

This research was carried out in particular by Henri Voedts, Phuong Chi Nguyen and Van Son Nguyen, under the supervision of Seung Hyun Cho, Han Remaut and Jean-François Collet, with the participation of Pauline Leverrier and Bogdan Iorga.

Article describing this research

Stress-induced membrane insertion at the β-barrel assembly machinery complex regulates BepA metalloprotease activity.

Voedts H, Nguyen PC, Nguyen VS, Leverrier P, Iorga BI, Cho SH, Remaut H, Collet JF

Nat Commun (2026) 17(1):10665