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Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
Reprint requests to: Dr. Jeffery W. Kelly, Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Toney Pines Road, BCC265, La Jolla, California 92037, USA; e-mail: jkelly{at}scripps.edu; fax: 858-784-9610.
Transthyretin (TTR) subunits were labeled with a charge-modifying tag to evaluate the possibility of subunit exchange between tetramers under physiological conditions. Starting with a mixture of two TTR homotetramers, one having all subunits tagged at the N termini and the other composed of untagged subunits, heterotetramer formation as a function of time and temperature was evaluated using ion exchange chromatography. The data indicate that the subunit exchange can occur under native conditions at physiological pH in vitro, albeit slowly. Wild-type TTR exchanges subunits on a timescale of days at 37°C and on a timescale of hours at 4°C. The familial amyloid polyneuropathy-associated variant V30M exchanges subunits at the same rate as wild-type TTR at 4°C but slower and less efficiently at 37°C. Small molecule tetramer stabilizers abolish TTR subunit exchange, supporting a dissociative mechanism.
Keywords: Transthyretin; amyloid; familial amyloid polyneuropathy; ion exchange chromatography
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