Abstract
The sensitivity of bacteriophage T4 lysozyme function to amino acid substitutions at defined positions in and around the longitudinal, hydrophobic strips of 9 alpha-helices was assessed after systematic replacement of each residue in the protein with a series of 13 amino acids. The hydrophobic strips were defined by identifying the longitudinal sectors in the helices with the highest mean residue hydrophobicities. Sensitivity to mutation (the percentage of replacements leading to loss of function) was calculated for each residue in the following positions: whole protein, helices, hydrophobic strips, other positions within the helices, and various positions within the hydrophobic strips as well as their extensions beyond the helices. Substitutions at positions in the hydrophobic strips led more frequently to loss of function than substitutions in the protein as a whole. One subset, the COOH-terminal hydrophobic strip residues, is apparently critical; substitutions of these residues (but not of their NH2-terminal counterparts) led at least as frequently to loss of function as substitutions of solvent-inaccessible residues, and nearly as frequently as substitutions of the most highly conserved residues.
Highlights
The sensitivity of bacteriophage T4 lysozyme function to amino acid substitutions at defined positions in and around the longitudinal, hydrophobic strips of 9 a-helices was assessed after systematic replacement of each residue in the protein with a series of 13 amino acids
Thesecritical residues are ones whose replacement with other residues frequently results in a loss of function
For purposes of understanding and engineering proteins, it would beuseful to be able to pick out such critical residues in a protein of known structure, without having to carry out systematic mutational studies
Summary
Hydrophobic positions about the helices of T4 lysozyme was not elevated above the uniform distribution found inthe. Two described as a,,and “distorted a” structures, which we did groups of residues, corresponding to the smallest residues in not evaluate [10, 11].In termsof sensitivity to substitutions, the hydrophobic strip, and thveirtual extensions of the COOH a-helical residues were typical of the protein as a whole; 16% termini of the hydrophobic strips exhibited scores 13 above of substitutions were deleterious. Within this group, though, their expected values. NH2-terminal COOH-terminal Smallest NH2 shoulders COOH should8e6rs NI&-terminaVl irtual COOH-terVmiirntuaal l Non-strip
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