(Press-News.org)
Ikoma, Japan—Gram-negative bacteria pose a significant threat to global health due to their high resistance to antibiotics compared to that of Gram-positive bacteria. Their formidable defensive capabilities stem from their outer membrane (OM), which acts as a selective barrier against harmful compounds. The OM is not merely a static shield but a dynamic structure crucial for the bacteria’s survival and virulence. Thus, understanding how the OM is built and maintained is critical in our battle against drug-resistant infections.
To construct such an effective protective layer, bacteria rely on specialized molecular machinery. The lipopolysaccharide transport (Lpt) system is a key player in this process, as it integrates functional lipopolysaccharide complexes into the OM. Although some components of this transport pathway, such as the LptDE complex, are known to be essential for bacterial survival, the precise mechanisms governing their assembly and maturation remain unclear.
In a recent study, a research team led by Assistant Professor Ryoji Miyazaki from the Nara Institute of Science and Technology (NAIST), Japan, made an important discovery toward a better understanding of these processes. Their study, made available online on July 16, 2025, and scheduled for publication on August 26, 2025, in Volume 44, Issue 8 of the journal Cell Reports, reveals the critical role of a small protein called LptM in maturing and stabilizing LptD, which, together with LptE, forms the LptDE complex. The study was co-authored by Mai Kimoto, Dr. Hidetaka Kohga, and Professor Tomoya Tsukazaki from NAIST.
The team employed a combination of advanced techniques to shed light on the function of LptM. They investigated the precise timing of various events during LptD maturation, demonstrating that LptM acts at a later stage, influencing already-folded LptD intermediates. Through comprehensive mutational analyses, they identified a short region of LptM, comprising fewer than ten amino acid residues, as essential for its purpose. The researchers then used cryo-electron microscopy to acquire a high-resolution structure of the Escherichia coli LptDEM complex. This analysis, combined with biochemical experiments, provided an unprecedented molecular view of how LptM directly interacts with and stabilizes the LptDE complex.
Their results revealed that LptM positions itself at a critical interface within LptD, suggesting its role in fine-tuning the structure of this protein for Lpt. This enhanced understanding of the LptDE assembly process has significant implications for future therapeutic advances. “Our study highlights the essential role of LptM, providing fundamental insights that may support antibiotic design, as the LptDE complex has been identified as a potential target for novel antibiotics,” states Dr. Miyazaki. “Thus, our findings contribute to the advancement of research that could guide future drug discovery.”
Beyond potential drug targets, this research also sheds important light on a broader principle in biology. “Our findings suggest that small proteins, many of which have been previously overlooked, may play critical roles in the assembly and regulation of larger membrane protein complexes. This opens up a new perspective in basic biology, underscoring the functional relevance of small proteins,” remarks Dr. Miyazaki.
Indeed, such results could open doors to new avenues for exploring the previously unrecognized functions of these “microproteins” in various cellular processes.
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Resource
Title: Structural basis of lipopolysaccharide translocon assembly mediated by the small lipoprotein LptM
Authors: Ryoji Miyazaki, Mai Kimoto, Hidetaka Kohga, and Tomoya Tsukazaki
Journal: Cell Reports
DOI: 10.1016/j.celrep.2025.116013
Information about the Structural Life Science Laboratory can be found at the following website: https://bsw3.naist.jp/tsukazaki/en.html
About Nara Institute of Science and Technology (NAIST)
Established in 1991, Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Known as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become tomorrow's leaders in science and technology.
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