The importance of loop length in the folding of an immunoglobulin domain

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Abstract
Immunoglobulin (Ig)-like proteins have been shown to fold following formation of a nucleus comprising interactions between residues that are distant in the primary sequence. What role do the loops connecting these nucleus residues play? Here, the importance of loops connecting β-strands in different sheets of the Ig fold is investigated, by insertion of five glycine residues into the B–C loop of an Ig domain from human titin, TI I27. The folding pathway of this elongated ‘pseudo wild-type’ TI I27 is probed using protein engineering and Φ-value analysis. The Φ-values calculated for mutants within the pseudo wild-type protein indicate that the folding nucleus in wild-type TI I27 is conserved, supporting the hypothesis that the inter-sheet loop is not critical to the formation of a long-range folding nucleus.