Protein plasticity to the extreme: changing the topology of a 4-α-helical bundle with a single amino acid substitution

• DOI: 10.1016/s0969-2126(99)80081-1
• Publication Date: 2002-07-26T00:27:01Z
• Authors: Nicholas M Glykos; Gianni Cesareni; Michael Kokkinidis
• Keywords: Models, Molecular; 0301 basic medicine; Protein Folding; topology; Static Electricity; fold; RNA-Binding Proteins; Crystallography, X-Ray; Rop; Protein Structure, Secondary; Protein Structure, Tertiary; 03 medical and health sciences; Bacterial Proteins; Structural Biology; Mutation; Thermodynamics; bundle; Molecular Biology; Dimerization; mutagenesis

Conventional wisdom has it that two proteins sharing 98.4% sequence identity have nearly identical three-dimensional structures. Here we provide a counter-example to this statement by showing that a single amino acid substitution can change the topology of a homodimeric 4-alpha-helical bundle protein.We have determined the high-resolution crystal structure of a 4-alpha-helical protein with a single alanine to proline mutation in the turn region, and show that this single amino acid substitution leads to a complete reorganisation of the whole molecule. The protein is converted from the canonical left-handed all-antiparallel form, to a right-handed mixed parallel and antiparallel bundle, which to the best of our knowledge and belief represents a novel topological motif for this class of proteins.The results suggest a possible new mechanism for the creation and evolution of topological motifs, show the importance of loop regions in determining the allowable folding pathways, and illustrate the malleability of protein structures.