ALTERATIONS IN THE SECONDARY STRUCTURE OF MUTANT TRANSTHYRETINS ASSOCIATED WITH FAMILIAL AMYLOIDOTIC POLYNEUROPATHY AFTER PROTEOLYSIS BY NEUTROPHIL SERINE PROTEASES

Transthyretin (TTR), a tetrameric protein with two extensive beta-shee ts in each monomer, is the precursor protein of the amyloid fibril dep osits in persons with an autosomal dominantly inherited disease termed familial amyloidotic polyneuropathy (FAP or ATTR). The TTR isolated f rom four affected heterozygous individuals, each with a different muta tion or at a different stage of disease war examined with respect to a lteration in conformation after exposure to human neutrophil elastase (HNE) or cathepsin G by circular dichroism (CD), and their spectra com pared to normal. Normal untreated TTR exhibits a negative minimum at 2 14 nm by CD analysis. After enzymatic digestion, minor changes are obs erved. The mutant TTRs differ from normal with a more marked alteratio n in beta conformation after digestion. The degree of CD alteration of mutant TTR digested with HNE seemed to correlate with the severity of disease in each kinship. In addition, mutant TTRs that are more hydro philic have more marked CD alteration.