Residue-Dependent Thermodynamic Cost and Barrel Plasticity Balances Activity in the PhoPQ-Activated Enzyme PagP of Salmonella typhimurium

Biochemistry
Bharat Ramasubramanian Iyer, Radhakrishnan Mahalakshmi

Abstract

PagP is an eight-stranded transmembrane β-barrel enzyme indispensable for lipid A palmitoylation in Gram-negative bacteria. The severity of infection by pathogens, including Salmonella, Legionella, and Bordetella, and resistance to antimicrobial peptides, relies on lipid A remodeling by PagP, rendering PagP a sought-after drug target. Despite a conserved sequence, more robust palmitoylation of lipid A is observed in Salmonella typhimurium compared to Escherichia coli, a possible consequence of the differential regulation of PagP expression and/or specific activity. Work here identifies molecular signatures that demarcate thermodynamic stability and variances in catalytic efficiency between S. typhimurium (PagP-St) and E. coli (PagP-Ec) transmembrane PagP barrel variants. We demonstrate that Salmonella PagP displays a 2-fold destabilization of the barrel, while achieving 15-20 magnitude higher lipase efficiency, through subtle alterations of lipid-facing residues distal from the active site. We find that catalytic properties of these homologues are retained across different lipid environments such as micelles, vesicles, and natural extracts. By comparing thermodynamic stability with activity of selectively designed mutants, we c...Continue Reading

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Citations

Mar 8, 2016·Biochimica Et Biophysica Acta·Vito De PintoRadhakrishnan Mahalakshmi
Aug 16, 2016·Biochemistry·Bharat Ramasubramanian Iyer, Radhakrishnan Mahalakshmi
Nov 5, 2016·Biochimica Et Biophysica Acta·Svetlana Rajkumar Maurya, Radhakrishnan Mahalakshmi
Jun 9, 2017·The Journal of Biological Chemistry·Bharat Ramasubramanian IyerRadhakrishnan Mahalakshmi
Dec 23, 2017·BMC Biology·Bob SchiffrinSheena E Radford
Oct 22, 2015·The Journal of Biological Chemistry·Svetlana Rajkumar Maurya, Radhakrishnan Mahalakshmi
Jan 8, 2021·Protein Science : a Publication of the Protein Society·Pankaj B Tiwari, Radhakrishnan Mahalakshmi
Oct 5, 2018·Biochemistry·Bharat Ramasubramanian IyerRadhakrishnan Mahalakshmi

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