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Science 28 September 2001:
Vol. 293. no. 5539, pp. 2459 - 2462
DOI: 10.1126/science.1062245
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Reports

Trans-Suppression of Misfolding in an Amyloid Disease

Per Hammarström, Frank Schneider, Jeffery W. Kelly*

The transthyretin (TTR) amyloid diseases, representative of numerous misfolding disorders, are of considerable interest because there are mutations that cause or suppress disease. The Val30 rightarrow  Met30 (V30M) TTR mutation is the most prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas a Thr119 rightarrow  Met119 (T119M) mutation on the second TTR allele protects V30M carriers from disease. Here, we show that the incorporation of one or more T119M TTR subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation. Dissociation is required for amyloid formation, so these findings provide a molecular explanation for intragenic trans-suppression of amyloidosis. The data also suggest a potential therapeutic strategy, provide insight into tissue-specific deposition and amyloid composition, and support the validity of the amyloid hypothesis in human disease.

Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road BCC265, La Jolla, CA 92037, USA.
*   To whom correspondence should be addressed. E-mail: jkelly{at}scripps.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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F. L. Palhano, L. P. Leme, R. G. Busnardo, and D. Foguel (2009)
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Human-Murine Transthyretin Heterotetramers Are Kinetically Stable and Non-amyloidogenic: A LESSON IN THE GENERATION OF TRANSGENIC MODELS OF DISEASES INVOLVING OLIGOMERIC PROTEINS.
N. Reixach, T. R. Foss, E. Santelli, J. Pascual, J. W. Kelly, and J. N. Buxbaum (2008)
J. Biol. Chem. 283, 2098-2107
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L55P Transthyretin Accelerates Subunit Exchange and Leads to Rapid Formation of Hybrid Tetramers.
C. A. Keetch, E. H. C. Bromley, M. G. McCammon, N. Wang, J. Christodoulou, and C. V. Robinson (2005)
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Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis.
N. S. Green, T. R. Foss, and J. W. Kelly (2005)
PNAS 102, 14545-14550
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Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation.
S. S. Ray, R. J. Nowak, R. H. Brown Jr., and P. T. Lansbury Jr. (2005)
PNAS 102, 3639-3644
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Does the Cytotoxic Effect of Transient Amyloid Oligomers from Common Equine Lysozyme in Vitro Imply Innate Amyloid Toxicity?.
M. Malisauskas, J. Ostman, A. Darinskas, V. Zamotin, E. Liutkevicius, E. Lundgren, and L. A. Morozova-Roche (2005)
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The Crystal Structure of Transthyretin in Complex with Diethylstilbestrol: A PROMISING TEMPLATE FOR THE DESIGN OF AMYLOID INHIBITORS.
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The Dominant white, Dun and Smoky Color Variants in Chicken Are Associated With Insertion/Deletion Polymorphisms in the PMEL17 Gene.
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Assembly of the Yeast Prion Ure2p into Protein Fibrils: THERMODYNAMIC AND KINETIC CHARACTERIZATION.
N. Fay, Y. Inoue, L. Bousset, H. Taguchi, and R. Melki (2003)
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Direct Observation of Amyloid Fibril Growth Monitored by Thioflavin T Fluorescence.
T. Ban, D. Hamada, K. Hasegawa, H. Naiki, and Y. Goto (2003)
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Structure-Activity Relations of Successful Pharmacologic Chaperones for Rescue of Naturally Occurring and Manufactured Mutants of the Gonadotropin-Releasing Hormone Receptor.
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Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics.
P. Hammarstrom, R. L. Wiseman, E. T. Powers, and J. W. Kelly (2003)
Science 299, 713-716
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Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity.
P. Hammarstrom, X. Jiang, A. R. Hurshman, E. T. Powers, and J. W. Kelly (2002)
PNAS 99, 16427-16432
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Protein Origami: Therapeutic Rescue of Misfolded Gene Products.
P. M. Conn, A. Leanos-Miranda, and J. A. Janovick (2002)
Mol. Interv. 2, 308-316
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Induction of Protein Conformational Change in Mouse Senile Amyloidosis.
Y. Xing, A. Nakamura, T. Korenaga, Z. Guo, J. Yao, X. Fu, T. Matsushita, K. Kogishi, M. Hosokawa, F. Kametani, et al. (2002)
J. Biol. Chem. 277, 33164-33169
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Progress in transthyretin fibrillogenesis research strengthens the amyloid hypothesis.
A. Chakrabartty (2001)
PNAS 98, 14757-14759
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