Patsiarika, Anastasia; (2025) Neuropilin-1 and the immune system; the role of TGFβ1. Doctoral thesis (Ph.D), UCL (University College London).

Text Patsiarika PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 June 2026. Download (9MB)

Abstract

Transforming Growth Factor β1 (TGFβ1) is a cytokine implicated in many physiological processes such as cell proliferation and differentiation, apoptosis and immune system regulation. Neuropilin-1 (NRP1), a transmembrane co-receptor of physiological proteins including class III Semaphorins and Vascular Endothelial Growth Factor A (VEGFA), is also involved in the abovementioned processes. Early studies have indicated the ability of NRP1 to interact with TGFβ1 and have highlighted the synergetic role of the two proteins in driving cancer, infection and autoimmune diseases, like multiple sclerosis. To date, little is known about the nature of the interaction and its importance. The current study has used Surface Plasmon Resonance (SPR) to show that the active form of TGFβ1 interacts with the b1 domain NRP1 with a KD of 128nM. The small molecule EG00229 was found able to inhibit the interaction both in SPR and in the murine macrophage cell line Raw264.7, where it inhibited the activation of the canonical TGFβ1 pathway, mediated by pSmad2. Interestingly, it was shown that a type II beta turn of TGFβ1 interacts with the b1 domain of NRP1. Peptide 2 (Ac-I(CYYVGRKPKC)EQLSNMINH2), a peptide mimicking the original beta turn region was found to interact with the b1 domain both in SPR and in NMR titration experiments. An Alanine Scan Mutagenesis analysis indicated that the residues R7 and K8 are the most important for the interaction, as their mutation led to a complete loss of binding ability.

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