Does one folding defect lead to another? The importance of quaternary structure in transthyretin-mediated inhibition of beta-amyloid aggregation

BIOT 479

Lin Liu, linliu@wisc.edu, Jie Hou, and Regina M. Murphy, murphy@che.wisc.edu. Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706
Aß aggregation and its subsequent deposition as fibrils is the underlying cause of Alzheimer's disease. Transgenic mice studies suggest that transthyretin (TTR), a homotetrameric protein in blood and cerebrospinal fluid, interacts directly with Aß to inhibit its toxicity. We report results from biophysical analysis of Aß aggregation kinetics in the presence of plasma-derived TTR (pTTR). At substoichiometric ratios, pTTR drastically decreased the rate of aggregation. The data support a hypothesis wherein pTTR preferentially binds to aggregated Aß and arrests further growth. Recombinant TTR (rTTR), produced in E. coli, folded into the correct secondary structure and assembled into stable tetramers. However, rTTR failed to inhibit Aß aggregation and showed no binding to Aß. pTTR had higher thermal and acid stabilities and fewer accessible hydrophobic sites than rTTR. We concluded that rTTR, folding in vitro without the aid of chaperones, had subtle folding defects that damaged its ability to inhibit Aß aggregation.
 

Biophysical and Biomolecular Symposium: Protein Aggregation
2:00 PM-5:25 PM, Thursday, August 23, 2007 BCEC -- 107C, Oral

Division of Biochemical Technology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007