Structural studies and characterisation of Kir7.1 and its role in retinal disease

O'Malley, Niamh Mary (2024) Structural studies and characterisation of Kir7.1 and its role in retinal disease. PhD thesis, Birkbeck, University of London.

Abstract

Inward rectifying potassium channel 7.1 (Kir7.1) is a vital ion channel involved in maintaining cellular homeostasis and electrical signalling across various tissues and organs. Dysfunctions in Kir7.1 have been linked to rare retinal diseases, including Snowflake Vitreoretinal Degeneration (SVD) and Leber Congenital Amaurosis. Here, we resolved three cryo-EM structures of Kir7.1 that elucidate channel activation and how a R162W mutation contributes to SVD. While PIP2 is known to activate all human Kir channels by inducing conformational changes, the observed structures of Kir7.1 did not exhibit docking of the cytoplasmic domain as seen in other Kir channels. However, upon PIP2 binding to Kir7.1, the helix bundle crossing widens producing an open channel pore. The opening of the channel without docking of the cytoplasmic domain represents a novel mechanism for Kir channel activation. Cryo-EM analysis of the R162W mutation, responsible for SVD, revealed a structure with a more constricted pore compared to the wild type structure. The presence of the tryptophan residue at position 162 appears to impede potassium ion flow, contributing to the loss of Kir7.1 function and the pathology of SVD, providing a possible mechanism for the basis of the disease. By providing detailed insights into Kir7.1's overall architecture, channel gating, and involvement in retinal diseases, this thesis significantly contributes to our understanding of Kir7.1's structure-function relationship and regulatory mechanisms.

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