Membrane Binding and Dimerization of Fibroblast Growth Factor 2

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http://urn.fi/URN:NBN:fi:hulib-201904261781
Title: Membrane Binding and Dimerization of Fibroblast Growth Factor 2
Author: Kuisma, Juho
Contributor: University of Helsinki, Faculty of Science
Publisher: Helsingin yliopisto
Date: 2019
Language: eng
URI: http://urn.fi/URN:NBN:fi:hulib-201904261781
http://hdl.handle.net/10138/301282
Thesis level: master's thesis
Discipline: Teoreettinen fysiikka
Abstract: Fibroblast growth factor 2 (FGF2) is a protein conserved in mammals with multiple established functions in human biology. It acts as a mitogen promoting cell division and is also a known angiogenic factor. FGF2 has been linked with tumor cell proliferation due to its pro-angiogenic capability. However, in order to perform these functions FGF2 needs to be secreted outside the cell membrane. Secretion of proteins usually happens through the Golgi apparatus as a signal peptide-dependent process. FGF2 has been shown not to have a signal peptide needed for the secretion. Recently, a signal peptide-independent secretion pathway for FGF2 was suggested. The hypothesis is that FGF2 monomers bind to the intracellular leaflet of the cell membrane via interactions with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids. On the membrane surface, FGF2 monomers are then assumed to aggregate and form larger oligomers. These oligomers are thought to form a pore through which other FGF2 monomers can secrete into the extracellular space. As to FGF2-FGF2 binding needed in oligomerization, currently only one stable dimerization interface is known. In this interface, the key interaction is a disulfide bridge between cysteines C95-C95 stabilizing the complex. In this thesis, I studied the first two steps of the hypothesized secretion pathway using molecular dynamics (MD) and Monte Carlo (MC) simulations. First, I studied FGF2 binding to a cell membrane through umbrella sampling simulations and determined free energies for the membrane binding of FGF2 with different membrane concentrations of cholesterol and PI(4,5)P2 . The free energy was shown to inversely correlate with both quantities. Second, I investigated FGF2 dimerization to find new candidates for the monomer-monomer interfaces needed for FGF2 oligomerization. The dimerization was studied using atomistic MC simulations and coarse-grained MD simulations. Two new promising interfaces were identified, which could play a key role in the higher order oligomerization of FGF2 monomers.


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