Structure, function and aggregation of the lens alpha-crystallins
EMSL Project ID
50641
Abstract
We are applying emerging methods in single particle CryoEM to advance our understanding the molecular mechanisms leading to cataract formation (the leading cause of blindness in the world). The focus of this research proposal is to understand the mechanism by which the major cytosolic proteins of the lens, known as crystallins, contribute to lens transparency and how age-related changes to these proteins contribute to cataract formation. The lens cytosol is super-saturated by three classes of protein, known as Alpha, Beta, and Gamma-crystallins. The high concentrations of Beta/Gamma-crystallins establish the appropriate refractive index of the lens to accurately focus light. a-crystallins makes up 40% of the lens cytosolic protein content, and functions as an ATP-independent molecular chaperone (i.e., protein hold-ase). The chaperone activity of Alpha-crystallin is thought to guard against age-related aggregation events that would otherwise disrupt the delicate proteostasis of the lens. However, the life-long accumulation of chemical modifications and/or post-translational modification induce complex forms of protein-protein interactions and lead to their direct aggregation and/or client-induced co-aggregation, and ultimately cataract formation. We aim to harness the powers of single particle CryoEM to develop an atomic-level understanding of the dynamic mechanisms that enable Alpha-crystallin chaperone activity and the mechanistic progressions leading to various aggregation states that are responsible for cataract formation.
Project Details
Start Date
2019-01-14
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members