Modulation of N- to C-terminal interactions enhances protein stability

Although, several factors have been attributed to thermostability, the stabilization strategies used by proteins are still enigmatic. Studies on recombinant xylanase which has the ubiquitous (\b{eta}/{\alpha})8 TIM (Triosephosphate isomerase) barrel fold showed that, just a single extreme N-terminus mutation (V1L) markedly enhanced the thermostability by 5 {\deg}C without loss of catalytic activity whereas another mutation, V1A at the same position decreased the stability by 2 {\deg}C. Based on computational analysis of their crystal structures including residue interaction network, we established a link between N- to C-terminal contacts and protein stability. We demonstrate that augmenting of N- to C-terminal non-covalent interactions is associated with the enhancement of protein stability. We propose that the strategy of mutations at the termini could be exploited with a view to modulate stability without compromising on enzymatic activity, or in general, protein function, in diverse folds where N- and C-termini are in close proximity. Finally, we discuss the implications of our results for the development of therapeutics involving proteins and for designing effective protein engineering strategies.