# Solid-state NMR Structural Characterizations of Polymorphic Transthyretin Amyloids

> **NIH NIH R01** · EAST CAROLINA UNIVERSITY · 2020 · $219,144

## Abstract

Protein misfolding and amyloid formation is implicated in numerous diseases such as amyloidoses,
prion and Alzheimer's diseases. Prion disease is unique in that the natively folded prion protein forms
aggregates with distinct molecular conformations (prion strains), which underlie different disease
phenotypes.1-3 The prion strain may be encoded in the primary sequence and mutations of the protein
induce different strains, causing distinct disease phenotypes. Recent studies have suggested the
strain hypothesis is applicable to other amyloid diseases that also manifest diverse disease
phenotypes.1,2,4,5 Nonprion amyloids were shown to exhibit a wide conformational diversity,6-10 which
may be linked to the phenotype variations. However, little is known about molecular basis of the
diverse misfolding pathways and structural diversity of amyloid. Structural studies of the amyloid are
essential to understanding molecular mechanism of amyloid diversity. Effect of the pathogenic
mutations on misfolding pathway should also be examined. The systematic biophysical studies have,
however, been challenging for previously investigated amyloidogenic proteins due to the limited
number of pathogenic mutations associated with distinct disease phenotypes. In addition, the most
extensively studied polypeptides, β-amyloid and α-synuclein associated with Alzheimer's and
Parkinson's diseases respectively, are natively unfolded, rendering the polypeptides not amenable for
mechanistic studies of the initial conformational transition (misfolding). This research program is aimed
at investigating amyloid formation mechanisms of a natively folded protein, transthyretin (TTR), using
solid-state NMR. Transthyretin (TTR) is one of more than 30 human proteins that undergo an aberrant
conformational change and misassemble into β-structured amyloid. Amyloid formation of wild type and
more than 100 mutant forms of TTR are known to cause various amyloidoses with enormous
phenotype diversity.11 The main hypothesis of this proposal is that pathogenic mutant forms of TTR
may have distinct misfolding pathways, adopting diverse amyloid conformations with different toxic
activities, which may result in diverse disease phenotypes and tissue-selective depositions. The
hypothesis will be tested through the structural characterization of amyloid derived from wild-type and
various pathogenic mutant forms of TTR. In particular, solid-state NMR with innovative labeling
schemes will provide valuable insights into amyloid diversity. Specific aims of the proposal are to
explore: (1) Native-like structural features of amyloid core regions. (2) Conformational changes of the
loop regions during amyloid formation. (3) Quaternary structure of WT and mutant forms of TTR
amyloid. Mechanistic understanding of the misfolding and amyloid formation pathways would be
critical to developing effective therapeutic strategies for TTR amyloidoses.

## Key facts

- **NIH application ID:** 9915975
- **Project number:** 5R01NS097490-04
- **Recipient organization:** EAST CAROLINA UNIVERSITY
- **Principal Investigator:** KWANG HUN LIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $219,144
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915975

## Citation

> US National Institutes of Health, RePORTER application 9915975, Solid-state NMR Structural Characterizations of Polymorphic Transthyretin Amyloids (5R01NS097490-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9915975. Licensed CC0.

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