# Structure and stability in proteins and analogues

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $87,705

## Abstract

SUMMARY
 We want to elucidate modes of polypeptide assembly that are important for biological
function and associated with human disease but are difficult to characterize via standard
experimental approaches. In each case, we wish to understand the non-covalent forces that
underlie the assembly mode. Because of differences among the types of assembly we are
studying, the experimental approaches we adopt are variable.
 Routine access to circular dichroism (CD) data is critical for research progress in each area.
We request funds to replace our current CD instrument, which is 10 years old, inoperable and
can no longer be serviced because the manufacturer went out of business.
 One goal is to characterize quaternary structures formed by single-pass transmembrane
(SPTM) α-helices that are constituents of oligomeric cell-surface receptors. Crystallographic
data are available only for the SPTM α-helix of immune receptor component DAP12. There is no
high-resolution structural information for alternative geometries of SPTM α-helix assemblies that
are thought to be associated with different receptor activation states. We are applying racemic
crystallization and micro-electron diffraction (via collaboration) to this structural challenge, and
we are exploring protein-based “picodiscs” as hosts for SPTM α-helix assemblies.
 A second goal is to understand how sequence, composition and dimensions influence
stability of polypeptides in the amyloid state. The β-sheet-rich structures that are common to
disease-associated amyloid fibrils are distinct from tertiary and quaternary structures commonly
found among soluble proteins. The techniques commonly used to elucidate sequence-stability
relationships among soluble proteins are not readily applied to amyloid fibrils. A soluble amyloid
model would streamline fundamental studies of amyloid state stability.
 The third goal is to understand the forces that lead to liquid-liquid phase separation
(LLPS) mediated by proteins in the FUS (“fused in sarcoma”) family. The loose associations
between polypeptide chains in the protein-rich liquid phase are not well understood. Such
phases can transition to amyloid-like assemblies, which are associated with illnesses such as
ALS. We seek to model LLPS of FUS family proteins with synthetic peptides in order to conduct
incisive tests of recent mechanistic proposals and to evaluate the role of amino acid sequence
and stereochemistry in LLPS and the transition to more ordered and pathogenic assemblies.

## Key facts

- **NIH application ID:** 10139875
- **Project number:** 3R01GM061238-21S1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SAMUEL H. GELLMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $87,705
- **Award type:** 3
- **Project period:** 2000-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10139875

## Citation

> US National Institutes of Health, RePORTER application 10139875, Structure and stability in proteins and analogues (3R01GM061238-21S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10139875. Licensed CC0.

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