Structural analysis of X-Linked Retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function

Ramsay, Ewan P. and Collins, Richard F. and Owens, Thomas W. and Siebert, C. Alistair and Jones, Richard P. O. and Wang, Tao and Roseman, Alan M. and Baldock, Clair (2016) Structural analysis of X-Linked Retinoschisis mutations reveals distinct classes which differentially effect retinoschisin function. Human Molecular Genetics, 25 (24). pp. 5311-5320. ISSN 1460-2083

[img]
Preview
Text
Published Version
Available under the following license: Creative Commons Attribution.

Download (2MB) | Preview
Official URL: https://doi.org/10.1093/hmg/ddw345

Abstract

Retinoschisin, an octameric retinal-specific protein, is essential for retinal architecture with mutations causing X-linked retinoschisis (XLRS), a monogenic form of macular degeneration. Most XLRS-associated mutations cause intracellular retention, however a subset are secreted as octamers and the cause of their pathology is ill-defined. Therefore, here we investigated the solution structure of the retinoschisin monomer and the impact of two XLRS-causing mutants using a combinatorial approach of biophysics and cryo-EM. The retinoschisin monomer has an elongated structure which persists in the octameric assembly. Retinoschisin forms a dimer of octamers with each octameric ring adopting a planar propeller structure. Comparison of the octamer with the hexadecamer structure indicated little conformational change in the retinoschisin octamer upon dimerization, suggesting that the octamer provides a stable interface for construction of the hexadecamer. The H207Q XLRS-associated mutation was found in the interface between octamers and destabilized both monomeric and octameric retinoschisin. Octamer dimerization is consistent with the adhesive function of retinoschisin supporting interactions between retinal cell layers, so disassembly would prevent structural coupling between opposing membranes. In contrast, cryo-EM structural analysis of the R141H mutation at ~4.2Å resolution was found to only cause a subtle conformational change in the propeller tips, potentially perturbing an interaction site. Together, these findings support distinct mechanisms of pathology for two classes of XLRS-associated mutations in the retinoschisin assembly.

Item Type: Journal Article
Additional Information: The HMG Advance Access version (not this version) was first published on October 23, 2016. © The Author 2016. Published by Oxford University Press as an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |The dataset underpinning the findings described in this paper can be accessed at : https://www.rcsb.org/pdb/explore/explore.do?structureId=5N6W |
Keywords: X-linked retinoschisis, cryoEM, macular degeneration, retinoschisin
Faculty: ARCHIVED Faculty of Science & Technology (until September 2018)
Depositing User: Dr Richard P O Jones
Date Deposited: 11 Nov 2016 15:50
Last Modified: 14 Nov 2019 16:11
URI: http://arro.anglia.ac.uk/id/eprint/701103

Actions (login required)

Edit Item Edit Item