Lookup NU author(s): Susan Fridd,
Professor Jeremy Lakey
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The pore-forming domains of members of a family of bacterial toxins, colicins N and A, share > 50% sequence identity, identical folds and yet display strikingly different behavior in acid conditions. At low pH colicin A forms a molten globule state while colicin N retains a native fold. This is relevant to in vivo activity since colicin A requires acidic phospholipids for its toxic activity but colicin N does not. The pI of colicin A (5.25) is far lower than that of colicin N (10.2) because colicin A contains seven extra aspartate residues. We first introduced separately each of these acidic amino acids into homologous sites in colicin N, but none caused destabilization at low pH. However, in the reverse experiment, the sequential replacement of these acidic side chains of colicin A by alanine revealed six sites where this change destabilized the protein at neutral pH. Some of these residues, which each contribute less than 4% to the total negative charge, appear to stabilize the protein via a network of hydrogen bonds and charge pairs which are sensitive to protonation. Other residues have no clear interactions that explain their importance. The colicin A is thus a protein that relies upon acid sensitive interactions for its stability at neutral pH and its in vivo activity.
Author(s): Fridd SL, Lakey JH
Publication type: Article
Publication status: Published
ISSN (print): 0006-2960
ISSN (electronic): 1943-295X
Publisher: American Chemical Society
PubMed id: 11814351
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