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Structural Analysis of human retinal ABCA4 using single particle cryo-electron microscopy


EMSL Project ID
51243

Abstract

Stargardt disease (STGD1) is an autosomal recessive, early-onset macular dystrophy associated with reduced visual acuity and a progressive loss in vision. The gene responsible for STGD1 encodes ABCA4, a member of the ABCA subfamily of ATP binding cassette (ABC) transporters. ABCA4, present in rod and cone photoreceptor disc membranes, actively transports N-retinylidene-phosphatidyethanolamine (N-ret-PE) from the lumen to the cytoplasmic leaflet of disc membranes following photoexcitation. Disease-associated, loss-of-function mutations cause the accumulation of toxic retinoid compounds leading to photoreceptor cell death and severe visual impairment. ABCA4 is the only known mammalian ABC importer. The structure, substrate binding sites, and transport mechanisms are unknown. The aim of this project is to determine the structure of ABCA4 in its apo form and in complex with N-ret-PE and AMP-PNP by cryo-electron microscopy. This information will provide novel insight into the role of ABCA4 in vision and the molecular basis for STGD1.

Project Details

Start Date
2020-01-15
End Date
2021-03-17
Status
Closed

Team

Principal Investigator

Robert Molday
Institution
The University of British Columbia

Team Members

Jessica Fernandes Scortecci
Institution
The University of British Columbia

Theo Humphreys
Institution
Oregon Health & Science University

Irina El Khoury
Institution
Environmental Molecular Sciences Laboratory