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The oligomeric structure of human retinal protein retinoschisin provides insights into its molecular mechanisms underlying juvenile macular degeneration

Friday, September 18, 2015 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace
NCI
STRUCTBIO-11

* FARE Award Winner

Authors

  • G Tolun
  • C Vijayasarathy
  • RK Huang
  • JB Heymann
  • PA Sieving
  • AC Steven

Abstract

Retinoschisin (RS1) is a retinal cell surface protein that is predicted to be an adhesion complex preserving the structure and visual function of the retina. Mutations in RS1 gene lead to macular degeneration in young males, characterized by splitting of the inner retinal cell layers, disorganized synapses, reduced electrical response of the retina, and vision loss with age. Biochemical studies suggested that RS1 forms a homo-octameric ring, but in-depth structural studies have not been possible due to extremely low-yields of purified RS1. Hence, the molecular mechanisms underlying RS1 function remain unknown. We purified a sufficient quantity of full-length human RS1 for electron microscopy (EM). Using cryo-EM and single-particle reconstruction, we determined the structure of RS1 at ~4.6 Å. This structure shows that RS1 forms a stack of two octameric rings. This novel observation allows us to propose a molecular mechanism that describes the adhesion function of RS1 in keeping the retinal layers together: two RS1 single-rings found on the surfaces of two opposing retinal layers bind to each other to hold the two retinal layers together. The structure also shows that RS1 has two domains. The N-terminal domain is in the center of RS1-rings and is unstructured and/or very flexible. The C-terminal residues form a discoidin domain that forms binding pockets for many different ligands. Our glycan array data and bioinformatics analysis suggest that RS1 binds galactose. Hence, it may be interacting with glycoproteins to either activate intracellular pathways, or to potentiate further adhesion through an unknown mechanism.

Category: Structural Biology