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TIM Barrels

TIM Barrels
A map demonstrating the different levels of hydrogen exchange protection observed for peptides of a proteolytically digested TIM barrel are shown and then mapped onto the crystal structure on the right.

The (βα)8 TIM barrel motif is the most commonly observed fold in biology. TIM barrels are found in all three major kingdoms and in five of the six classes of enzymes. About 10% of all proteins with known three-dimensional structures contain at least one TIM barrel domain. The canonical (βα)8-barrel contains about 200-260 amino acids and is composed of eight βα-repeat units comprised of a β-strand and an anti-parallel α-helix connected by a βα-loop. In all known TIM barrels, the catalytic active residues are located at the C-terminal ends of the β-strands and in the βα-loops, while residues maintaining the stability of the fold are found in the β-strands and at the opposite end of the barrel in the αβ-loops. The similar topology and structure observed for (βα)8-barrel proteins often arises from vastly divergent amino acid sequences. Thus, TIM barrel proteins are an excellent system for assessing the contributions of the topology and the sequence in governing the folding pathway and the stability of the native structure. Although topology dictates the basic features of the folding free energy surface, we have found that large clusters of isoleucine, leucine and valine side chains between the β-barrel core and the α-helical shell correspond closely to cores of stability. Topology and sequence are both crucial to the folding and stability of these globular proteins.