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MacP bypass variants of Streptococcus pneumoniae PBP2a suggest a conserved mechanism for the activation of bifunctional cell wall synthases
Department of Microbiology, Harvard Medical School, Blavatnik Institute, Boston, Massachusetts, USA.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, Massachusetts, USA.
Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).ORCID-id: 0000-0001-5995-718x
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2023 (Engelska)Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, nr 6, artikel-id e0239023Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The peptidoglycan (PG) layer protects bacteria from osmotic lysis and defines their shape. The class A penicillin-binding proteins (aPBPs) are PG synthases that possess both glycan polymerization and crosslinking activities needed for PG biogenesis. In Gram-negative bacteria, aPBPs require activation by outer membrane lipoproteins, which are thought to stimulate their cognate synthase by inducing conformational changes that promote polymerase function. How aPBPs are controlled in Gram-positive bacteria is less clear. One of the few known regulators is MacP in Streptococcus pneumoniae (Sp). MacP is required for the activity of Sp PBP2a, but its mode of action has been obscure. We therefore selected for PBP2a variants capable of functioning in the absence of MacP. Amino acid substitutions that bypassed the MacP requirement for PBP2a function in vivo also activated its polymerase activity in vitro. Many of these changes mapped to the interface between the transmembrane (TM) helix and polymerase domain in a model PBP2a structure. This region is conformationally flexible in the experimentally determined structures of aPBPs and undergoes a structural transition upon binding the substrate-mimicking drug moenomycin. Our findings suggest that MacP promotes PG polymerization by altering the TM-polymerase domain interface in PBP2a and that this mechanism for aPBP activation may be broadly conserved. Furthermore, Sp cells expressing an activated PBP2a variant displayed heterogeneous shapes, highlighting the importance of proper aPBP regulation in cell morphogenesis.

Importance: Class A penicillin-binding proteins (aPBPs) play critical roles in bacterial cell wall biogenesis. As the targets of penicillin, they are among the most important drug targets in history. Although the biochemical activities of these enzymes have been well studied, little is known about how they are regulated in cells to control when and where peptidoglycan is made. In this report, we isolate variants of the Streptococcus pneumoniae enzyme PBP2a that function in cells without MacP, a partner normally required for its activity. The amino acid substitutions activate the cell wall synthase activity of PBP2a, and their location in a model structure suggests an activation mechanism for this enzyme that is shared with aPBPs from distantly related organisms with distinct activators.

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American Society for Microbiology, 2023. Vol. 14, nr 6, artikel-id e0239023
Nyckelord [en]
penicillin-binding proteins, peptidoglycan, cell envelope, cell wall
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Mikrobiologi inom det medicinska området
Identifikatorer
URN: urn:nbn:se:umu:diva-218565DOI: 10.1128/mbio.02390-23ISI: 001085326900001PubMedID: 37847021Scopus ID: 2-s2.0-85183091235OAI: oai:DiVA.org:umu-218565DiVA, id: diva2:1823799
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseKempestiftelsernaVetenskapsrådetTillgänglig från: 2024-01-03 Skapad: 2024-01-03 Senast uppdaterad: 2024-02-13Bibliografiskt granskad

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Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)Mikrobiologi inom det medicinska området

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