Abstract
Bacterial cell wall biosynthesis is an essential process that requires the coordinated activity of peptidoglycan biosynthesis enzymes within multi-protein complexes involved in cell division (the “divisome”) and lateral wall growth (the “elongasome”). MreC is a structural protein that serves as a platform during wall elongation, scaffolding other essential peptidoglycan biosynthesis macromolecules, such as penicillin-binding proteins. Despite the importance of these multi-partite complexes, details of their architecture have remained elusive due to the transitory nature of their interactions. Here, we present the crystal structures of the soluble PBP2:MreC core elongasome complex from Helicobacter pylori, and of uncomplexed PBP2. PBP2 recognizes the two-winged MreC molecule upon opening of its N-terminal region, revealing a hydrophobic zipper that serves as binding platform. The PBP2:MreC interface is essential both for protein recognition in vitro and maintenance of bacterial shape and growth. This work allows visualization as to how peptidoglycan machinery proteins are scaffolded, revealing interaction regions that could be targeted by tailored inhibitors.
Highlights
Bacterial cell wall biosynthesis is an essential process that requires the coordinated activity of peptidoglycan biosynthesis enzymes within multi-protein complexes involved in cell division and lateral wall growth
Proteins that are involved in PG biosynthesis associate in discrete multi-membered complexes that regulate cell division and cell wall elongation, and their inhibition or deregulation can lead to defects in cell shape, impaired growth, and often cell wall lysis and death[2, 3]
PBP2 and MreC interact through a hydrophobic zipper
Summary
Bacterial cell wall biosynthesis is an essential process that requires the coordinated activity of peptidoglycan biosynthesis enzymes within multi-protein complexes involved in cell division (the “divisome”) and lateral wall growth (the “elongasome”). Within the elongasome of a variety of bacteria including E. coli, Caulobacter crescentus, Bacillus subtilis, and Helicobacter pylori, PBPs have been shown to interact with, and be recruited by, the essential protein MreC, a bitopic membrane protein that is essential for cell shape[5,6,7,8,9,10,11,12,13] This process is orchestrated by the cytoplasmic actin homolog MreB, pointing to the existence of a multi-membered complex that spans cytoplasm, membrane, and periplasm. Despite the vast amount of functional evidence of the importance of the PBP:MreC interaction for bacterial cell wall formation, the absence of structural data regarding any periplasmic cell wallformation complex has hampered detailed studies of divisome or elongasome architecture Such complexes have been reported to only form at defined points in the cell cycle, and are fleeting in nature, fragile, and difficult to isolate[14]
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