Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid

Jeffery W. Kelly, Wilfredo Colon, Zhihong Lai, Hilal A. Lashuel, Jennifer Mcculloch, Sandra L. Mccutchen, Greta J. Miroy, Scott A. Peterson

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Human transthyretin (TTR) can be transformed into amyloid fibrils by partial acid denaturation to yield a monomeric amyloidogenic intermediate that self-associates into amyloid through quaternary structural intermediates, which are identified by sedimentation velocity methods. The monomeric amyloidogenic intermediate has substantial β-sheet structure with a nonnative but intact tertiary structure as discerned from spectroscopic methods. Proteolysis sensitivity studies suggest that the C-strand-loop-D- strand portion of TTR becomes disordered and moves away from the core of the β-sandwich fold upon formation of the monomeric amyloidogenic intermediate over the pH range 5.1-3.9. The single site mutations that are associated with early onset amyloid disease [familial amyloid polyneuropathy (FAP)] function by destabilizing tetrameric TTR. Under mild denaturing conditions, the FAP variants populate the monomeric amyloidogenic intermediate conformation, which assembles into amyloid, whereas wild-type TTR remains tetrameric and nonamyloidogenic. The FAP mutations do not significantly alter the native folded structure; instead, they appear to act by making the thermodynamics and perhaps the kinetics more favorable for formation of the amyloidogenic intermediate. Suppressor mutations have also been characterized that strongly stabilize tetrameric TTR and disfavor the formation of the monomeric amyloidogenic intermediate, thus inhibiting amyloid formation. The mechanistic details characterizing transthyretin amyloid fibril formation available from the biophysical studies outlined within have been utilized to develop a new therapeutic strategy for intervention in human amyloid disease. This approach features small molecules that bind with high affinity to the normal fold of transthyretin, inhibiting the quaternary and tertiary structural changes associated with the formation of the monomeric amyloidogenic intermediate that self-assembles into amyloid. Ligand binding to TTR stabilizes the native tetrameric fold, which is nonamyloidogenic.

Original languageEnglish
Pages (from-to)161-181
Number of pages21
JournalAdvances in Protein Chemistry
Volume50
Publication statusPublished - 29 Oct 1997
Externally publishedYes

Fingerprint

Prealbumin
Amyloid
Familial Amyloid Neuropathies
Genetic Suppression
Mutation
Proteolysis
Thermodynamics
Denaturation
Sedimentation
Ligands
Conformations
Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Kelly, J. W., Colon, W., Lai, Z., Lashuel, H. A., Mcculloch, J., Mccutchen, S. L., ... Peterson, S. A. (1997). Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. Advances in Protein Chemistry, 50, 161-181.

Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. / Kelly, Jeffery W.; Colon, Wilfredo; Lai, Zhihong; Lashuel, Hilal A.; Mcculloch, Jennifer; Mccutchen, Sandra L.; Miroy, Greta J.; Peterson, Scott A.

In: Advances in Protein Chemistry, Vol. 50, 29.10.1997, p. 161-181.

Research output: Contribution to journalArticle

Kelly, JW, Colon, W, Lai, Z, Lashuel, HA, Mcculloch, J, Mccutchen, SL, Miroy, GJ & Peterson, SA 1997, 'Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid', Advances in Protein Chemistry, vol. 50, pp. 161-181.
Kelly JW, Colon W, Lai Z, Lashuel HA, Mcculloch J, Mccutchen SL et al. Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. Advances in Protein Chemistry. 1997 Oct 29;50:161-181.
Kelly, Jeffery W. ; Colon, Wilfredo ; Lai, Zhihong ; Lashuel, Hilal A. ; Mcculloch, Jennifer ; Mccutchen, Sandra L. ; Miroy, Greta J. ; Peterson, Scott A. / Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid. In: Advances in Protein Chemistry. 1997 ; Vol. 50. pp. 161-181.
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