Biological complexity: bacterial double wall (Introduction)

by David Turell , Thursday, August 13, 2020, 18:35 (1563 days ago) @ David Turell

How it works is a feedback loop with complex lipoproteins:

https://www.nature.com/articles/d41586-020-02256-x?WT.ec_id=NATURE-202008&sap-outbo...

"Feedback inhibition occurs when the product of a metabolic pathway diminishes its own production by triggering a decrease in the activity of a key enzyme in the pathway. Such inhibition controls the production of lipopolysaccharide (LPS) molecules, which are an integral part of the outer membrane of some bacteria. It has long been suspected that the feedback signal responsible for regulating LPS biosynthesis is either LPS itself, or one of its precursors1. But, writing in Nature, Clairfeuille et al.2 add to a flurry of recent work3–5 showing that the membrane protein PbgA is the long-sought LPS signal transducer in the bacterium Escherichia coli. The current study extends our understanding of PbgA by providing a high-resolution structure of the protein bound to LPS.

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"Investigations published this year of how this pathway is regulated have produced a model in which PbgA on the inner membrane modulates the activity of LpxC by interacting with LapB — a protein that guides the enzyme FtsH to degrade LpxC1. So when levels of LPS are low, PbgA inhibits the interaction between LapB and FtsH in the inner membrane, stabilizing LpxC and promoting LPS biosynthesis. When the number of LPS molecules exceeds a threshold in the outer membrane, LPS transport across the bridge ceases. LPS accumulates on the external surface of the inner membrane, which can cause the formation of potentially lethal irregular membrane structures3. By sensing the accumulated LPS, PbgA can relax its inhibition of LapB–FtsH. LpxC can be degraded, thus diminishing LPS biosynthesis and restoring the phospholipid–LPS balance

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"Clairfeuille and co-workers’ structure reveals that PbgA binds the lipid A moiety through a linker domain, using an amino-acid sequence that has not been reported in any other LPS-binding protein. Mutations in this LPS-binding motif compromised PbgA function. In a final set of experiments, the authors demonstrated that a synthetic peptide based on this sequence could bind LPS and inhibit bacterial growth. Through rational design, they improved the peptide’s antibiotic spectrum and potency.

"The polymyxins bind lipid A by interacting with both of its phosphorylated sugars18, but PbgA binds to just one. The polymyxin antibiotic colistin is used as a last resort for treatment of infections in the clinic, but it can also increase outer membrane permeability, thereby sensitizing bacteria to more-effective antibiotics. Clairfeuille and co-workers’ show that the PbgA-derived peptide also sensitizes bacteria to other antibiotics, acts in synergy with colistin, and is not hampered by the LPS modifications catalysed by EptA."

Comment: Feedback loops are complex. This article shows are highly complex they can be. There is no way they c an appear as a complete mechanism by chance. They have to be designed all at once at the beginning of the organism. Only a diagram can explain all this complexity to you.