Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 28 September 2001:
Vol. 293. no. 5539, pp. 2459 - 2462
DOI: 10.1126/science.1062245
Prev | Table of Contents | Next

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Trapping the Monomer of a Non-amyloidogenic Variant of Transthyretin: EXPLORING ITS POSSIBLE USE AS A THERAPEUTIC STRATEGY AGAINST TRANSTHYRETIN AMYLOIDOGENIC DISEASES.
F. L. Palhano, L. P. Leme, R. G. Busnardo, and D. Foguel (2009)
J. Biol. Chem. 284, 1443-1453
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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)
J. Biol. Chem. 280, 41667-41674
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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)
J. Biol. Chem. 280, 6269-6275
   Abstract »    Full Text »    PDF »
The Crystal Structure of Transthyretin in Complex with Diethylstilbestrol: A PROMISING TEMPLATE FOR THE DESIGN OF AMYLOID INHIBITORS.
E. Morais-de-Sa, P. J. B. Pereira, M. J. Saraiva, and A. M. Damas (2004)
J. Biol. Chem. 279, 53483-53490
   Abstract »    Full Text »    PDF »
The Dominant white, Dun and Smoky Color Variants in Chicken Are Associated With Insertion/Deletion Polymorphisms in the PMEL17 Gene.
S. Kerje, P. Sharma, U. Gunnarsson, H. Kim, S. Bagchi, R. Fredriksson, K. Schutz, P. Jensen, G. von Heijne, R. Okimoto, et al. (2004)
Genetics 168, 1507-1518
   Abstract »    Full Text »    PDF »
Exploring amyloid formation by a de novo design.
R. A. Kammerer, D. Kostrewa, J. Zurdo, A. Detken, C. Garcia-Echeverria, J. D. Green, S. A. Muller, B. H. Meier, F. K. Winkler, C. M. Dobson, et al. (2004)
PNAS 101, 4435-4440
   Abstract »    Full Text »    PDF »
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)
J. Biol. Chem. 278, 30199-30205
   Abstract »    Full Text »    PDF »
Direct Observation of Amyloid Fibril Growth Monitored by Thioflavin T Fluorescence.
T. Ban, D. Hamada, K. Hasegawa, H. Naiki, and Y. Goto (2003)
J. Biol. Chem. 278, 16462-16465
   Abstract »    Full Text »    PDF »
Structure-Activity Relations of Successful Pharmacologic Chaperones for Rescue of Naturally Occurring and Manufactured Mutants of the Gonadotropin-Releasing Hormone Receptor.
J. A. Janovick, M. Goulet, E. Bush, J. Greer, D. G. Wettlaufer, and P. M. Conn (2003)
J. Pharmacol. Exp. Ther. 305, 608-614
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Protein Origami: Therapeutic Rescue of Misfolded Gene Products.
P. M. Conn, A. Leanos-Miranda, and J. A. Janovick (2002)
Mol. Interv. 2, 308-316
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Progress in transthyretin fibrillogenesis research strengthens the amyloid hypothesis.
A. Chakrabartty (2001)
PNAS 98, 14757-14759
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)