Structural and functional analysis of the polycystin protein family
The main focus of my group is the investigation of the molecular pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), a
common, inherited kidney disease that frequently leads to kidney failure and is associated with severe cardiovascular complications.
Genes causing this disease encode a family of proteins called the polycystins. Polycystin-1 is a large cell-surface protein of unknown
function. Using biochemical, molecular and structural techniques we aim to identify extracellular and intracellular ligands and show how they interact
with the wide variety of protein domains found in polycystin-1. In addition, mechanisms that target polycystin-1 to the cell surface are being
identified. The polycystins have been shown to function as a mechanosensitive cell surface calcium channel localised to the renal primary
cilium. We have recently shown that members of the classical receptor protein tyrosine phosphatase family interact with the polycystins in the
primary cilium which identifies a novel mechanism for mechanical regulation of ion channel function. Further work is focusing on identifying substrates
for these phosphatases and also other members of this large protein complex.
It is hoped that the elucidation of the normal function of polycystin-1 will identify key steps in the pathogenesis of ADPKD and potential ways of
modifying disease progression.
Funding
- The Wellcome Trust
- National Kidney Research Fund
Group members
- Cathy Boucher
- Sharon Mulroy
- Andy Needham
- Samantha Powell
- Seema Qamar
- Katie Thurston
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