# Mechanisms of structural plasticity, client interactions, and co-aggregation of the lens ⍺-crystallins

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $40,805

## Abstract

Project Summary
The ⍺-crystallins (⍺A- and ⍺B- isoforms) are essential for the development and lifelong transparency of the eye
lens. As molecular chaperones – members of the small heat shock protein family – the ⍺-crystallins play an
integral part of the stability of lens proteostasis and preventing the formation of age-related opacities (i.e., protein
aggregates) responsible for cataract formation. However, this system may become destabilized and/or
overwhelmed as a result of the long-lived nature of lens proteins, and ultimately contribute to disease
progression. Despite these fundamental roles in lens transparency and disease, there remains a critical gap in
our understanding of the molecular mechanisms by which the ⍺-crystallins function, and how these proteins
aggregate in response to aberrant (or age-related) conditions in the lens. A hallmark feature of the ⍺-crystallins
is a remarkable degree of structural plasticity that is driven by sub-domain interactions involving flexible N- and
C-termini, a feature that is thought to prevent crystallization under the highly concentrated environment of the
eye lens. This molecular plasticity also contributes to ⍺-crystallin chaperone function, allowing it to adapt to and
sequester a diverse range of destabilized proteins (aka clients) and prevent cytotoxic aggregation. However,
these same features of intrinsic dynamics have stymied previous efforts to obtain the detailed structural
characterizations (atomistic details) required to provide mechanistic insights into the function of these critical
components of the eye lens. The aims of this proposal will leverage recent advances in the state-of-the-art
methods of single particle CryoEM cryo-electron tomography (CryoET) – coupled with biophysical and functional
studies – in order to obtain high-resolution structural information regarding the mechanism of ⍺-crystallin
structural plasticity/polydispersity (Aim 1). Additional insights into the pathway(s) of chaperone/client co-
aggregation (Aim 2) will be garnered from NSEM, light scattering, and crosslinking-MS/MS methods. Success of
these aims will fill critical gaps in knowledge that have evaded the field for decades and provide detailed
mechanistic insights into the molecular basis of ⍺-crystallin’s hallmark of structural plasticity and how the lens
chaperone system becomes overwhelmed leading to cytotoxic protein aggregates such as those found in
cataract.

## Key facts

- **NIH application ID:** 10914127
- **Project number:** 5F31EY033226-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Adam Phillip Miller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $40,805
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914127

## Citation

> US National Institutes of Health, RePORTER application 10914127, Mechanisms of structural plasticity, client interactions, and co-aggregation of the lens ⍺-crystallins (5F31EY033226-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10914127. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*