How FtsZ and ZapA proteins drive bacterial cell division

Bacterial cell division – the process by which a single cell divides into two identical daughter cells – is orchestrated by a network of proteins. Central to this process is FtsZ – a protein that polymerises to form a ring-like structure called the Z-ring. This structure is stabilised by various FtsZ-associated proteins, including ZapA, which is highly conserved among bacterial species. Although ZapA is known to bind to FtsZ protofilaments and assist in Z-ring formation, the exact structural basis of their interaction has remained elusive – until now. 

Building on previous discoveries

A team of Japanese researchers, led by Professor Hiroyoshi Matsumura from the College of Life Sciences at Ritsumeikan University, has been investigating this interaction for years. Building on his previously published work on the structure of FtsZ protofilaments, Matsumura and his researchers wanted to find out how ZapA dynamically interacts with FtsZ to regulate cell division.

“FtsZ is a potential therapeutic target for bacterial infections. Hence, we wanted to understand how it maintains its dynamic nature while interacting with ZapA protein and the overall structure of the complex,” explains Matsumura.

Advanced imaging reveals structural insights

In their new study, published in Nature Communications, the team analysed FtsZ and ZapA proteins from Klebsiella pneumoniae. Using cryo-electron microscopy, they visualised the three-dimensional structure of the FtsZ-ZapA complex. They then employed high-speed atomic force microscopy to observe how the two proteins interact in real time.

The analysis revealed that ZapA forms a tetramer – four ZapA units that tether to FtsZ protofilaments – creating an asymmetric ladder-like structure. This arrangement positions a single FtsZ filament between two parallel FtsZ filaments on one side and a double anti-parallel protofilament on the other.

“In an anti-parallel protofilament, the filaments run alongside each other, but the subunits are aligned in opposite directions,” explains Matsumura. This configuration influences the alignment of FtsZ filaments and ultimately the formation of the Z-ring.

Dynamic and cooperative interactions

The researchers found that ZapA extensively interacts with FtsZ over large surface areas, inducing minor structural changes in FtsZ. They also discovered that the anti-parallel double filament exhibits electrostatic repulsion, which enhances the mobility of FtsZ filaments and helps them maintain their dynamic nature.

Most importantly, the interaction between ZapA and FtsZ was observed to be dynamic, characterised by repeated binding and dissociation. The team described this as cooperative binding. “Once ZapA binds to FtsZ, some structural change is observed. This makes the adjacent FtsZ molecule more accessible for the next ZapA molecule,” said Matsumura.

Implications for antibacterial research

By revealing how ZapA modulates the structure and dynamics of FtsZ, this study provides vital information for bacterial cell division. These findings could inform the development of new antibacterial drugs that block how harmful pathogenetic bacteria divides.

The research also showcases the power of combining cryo-electron microscopy with high-speed atomic force microscopy to expose complex cellular mechanisms. The research not only advances our understanding of an essential biological process but could also lead to potential future antibacterial treatments.