Role of clathrin light chains and other binding partners in generating functional diversity of clathrin heavy chains. (360G-Wellcome-102394_Z_13_Z)

This project aims to study clathrin heavy chain (CHC) binding interactions andhow these interactions diversify clathrin function. CHCs trimerise into a triskelion and can assemble into cage-like lattices on cellular membranes to sequester specific cargo for vesicular transport. There are two isoforms of clathrin heavy chains. Whereas CHC17 binds clathrin light chains (CLC), equivalent binding partners for CHC22 remain to be identified. CLCs modulate CHC17 cage assembly and mediate binding to Hip proteins, which recruit actin to the plasma membrane. Upregulation of both CLCs and Hip proteins are associated with forms of metastatic cancer. In this project, we will focus on three aspects of clathrin interactions: (1) We will investigate how CLC isoforms alter CHC17 clathrin trimer stability, tensile strength and disassembly - physical properties that can govern clathrin function and cargo selectivity (2) We will develop a high-throughput screen for an inhibitor of CLC-Hip interaction. This will provide the platform for drug development and research in metastatic cancer (3) A list of candidates for CHC22 interactions,derived from known binding partners, will be tested and binding regions will be mapped. This will give insight in CHC22 cellular function and allow for inhibitor screening for these interactions.