Serag et al. report the results of site-directed spin
labeling (SDSL) studies of inter-residue distances in native and amyloid-associated forms of transthyretin (TTR). TTR is associated with a number of amyloidoses, including senile systemic amyloidosis and familial amyloid polyneuropathy. The findings are of interest both for understanding the formation of amyloid fibrils by TTR and for understanding basic features of protein folding and design. An important question in this latter area is why proteins with high native b-sheet content do not assemble into amyloid. A systematic investigation into this question (Richardson&Richardson, 2002
) revealed that protein evolution has resulted in the inclusion of structural elements in natively folded proteins that "protect" edge β-strands from interactions with neighboring strands that might lead to adventitious and pathologic β-sheet formation. Typically, this type of protection is provided in cis
by amino acid sequence elements in the edge strand that inhibit or preclude...