# Structure, function and aggregation of lens α-crystallins by CryoEM

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $378,161

## Abstract

Project Summary
Light-scattering opacities responsible for age-related cataracts are a result of aggregation and precipitation of
the lens crystallins (α, β, and γ-crystallins). The α-crystallins (αA and αB isoforms) assemble as polydispersed
oligomeric complexes and function as ATP-independent molecular chaperones (i.e., protein hold-ases). Both of
these properties are thought to guard against aggregation events that would disrupt the delicate proteostasis of
the lens. It is known that environmental stress and chemical modifications that accrue over our lifetimes
destabilize the lens crystallins, and induce complex forms of protein-protein interactions that lead to
aggregation (amorphous and potentially fibril). However, a major hurdle to understanding the aggregation
pathways associated with cataracts, has been the lack of structural information on the major lens α-crystallins.
This gap in knowledge is due to the lack of effective methods to characterize the inherently polydispersed
structure of α-crystallin, the heterogeneity of chaperone-client aggregate formations, and evasiveness of fibril
aggregation states identified under physiological conditions. In this proposal, we describe our multidisciplinary
team-based approach, centered around the PI's expertise in the enabling technology of single particle CryoEM,
that will finally allow us to interrogate the basis of α-crystallin molecular plasticity. Specifically, we aim to define
high-resolution structures of the α-crystallins in their intrinsic polydispersed states (Aim 1), resolve key
structural intermediates (aka “pre-aggregation states”) induced under saturating client conditions (Aim 2), and
characterize a novel mechanism of fibrillogenesis discovered by our laboratory that is accessible to αB-
crystallin under cellular conditions (Aim 3). Structural studies will be complimented by biophysical and
functional characterization, performed in collaboration with Prof. Kirsten Lampi (OHSU), with the aim of
illuminating mechanistic principles that define α-crystallin structure, polydispersity and stability – which are
critical to avoidance of aggregation in the lens and therefore key to future success of drug-design strategies
targeted at controlling age-related cataracts (and a range of other human crystallin-opathies).

## Key facts

- **NIH application ID:** 10904875
- **Project number:** 5R01EY030987-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Stephen Loen Reichow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $378,161
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904875

## Citation

> US National Institutes of Health, RePORTER application 10904875, Structure, function and aggregation of lens α-crystallins by CryoEM (5R01EY030987-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10904875. Licensed CC0.

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