Yelland, TS;
(2015)
Structural studies of neuropilin-1.
Doctoral thesis , UCL (University College London).
Abstract
Neuropilin-1 (Nrp1) is ~130kDa multidomain type I transmembrane protein with no intrinsic enzymatic activity. Instead, acting as co-receptor in conjunction with other membrane proteins such as vascular endothelial growth factor receptors VEGFRs and plexins, neuropilins regulate key processes in vasculogenesis and neuronal cell development. The functional flexibility of neuropilins can be attributed to their multidomain composition. NRPs contain five extracellular domains: two CUB domains (homologous to complement binding factors) labelled a1 and a2; two coagulation factor domains, labelled b1 and b2, with homology to C1/C2 domains of factor FV/VIII; and a membrane-proximal MAM (meprin/antigen 5/ receptor tyrosine phosphotase μ) domain, labelled c. The cytoplasmic portion of a neuropilin molecule, comprises a small 44 residue-long domain that is structurally uncharacterized. Most research efforts have focused on the extracellular ligand binding a1a2b1b2 domains. This thesis will describe my PhD work which has focused on structural determination of the two poorly characterized domains of human neuropilin-1: MAM (c) domain - believed to be required for neuropilin dimerization, and the short cytoplasmic domain which is linked to VEGF signalling, NRP1 recycling, association with PDZ domain-containing intracellular proteins, and blood vessels permeability. This work utilised a variety of complimentary techniques including x-ray crystallography, NMR, ITC and CD shedding light on how these domains carry out their biological function. Furthermore, the potential medical significance of Nrp1 means that it is a valid anti-cancer therapeutic target. A number of co-crystallised structures are presented of the b1 domain in complex with small ligands in an on-going drug development collaboration with an industry partner.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Structural studies of neuropilin-1 |
| Event: | University College London |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1473466 |
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