A computational study on the membrane sculpting mechanism of missing-in-metastasis
Turppa, Emmi Maria Johanna (2017)
2017
Teknis-luonnontieteellinen koulutusohjelma
Luonnontieteiden tiedekunta - Faculty of Natural Sciences
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Hyväksymispäivämäärä
2017-02-08
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tty-201701191057
https://urn.fi/URN:NBN:fi:tty-201701191057
Tiivistelmä
Missing-in-metastasis (MIM) is an adaptor protein that connects the actin cytoskeleton to the plasma membrane. Its N-terminal domain, known as MIM IMD, is a member of the Bin-amphiphysin-Rvs (BAR) domain family, known for their ability to generate membrane curvature. More specifically, it is an inverse BAR (I-BAR) domain, generating negative curvature. MIM IMD is implicated in the formation of lamellipodia and filopodia, disassembly of actin stress fibers, and maintenance of adherence junctions. However, the exact membrane sculpting mechanism it employs has remained elusive.
So far MIM has been studied only experimentally. In this thesis, for the first time we employ molecular dynamics (MD) simulations to computationally address the membrane sculpting mechanism of MIM. We employ both atomistic and mesoscopic scale simulations, examining the behaviour of MIM IMD in the presence of lipid bilayers of different properties.
First, inspection of the crystal structure of the domain under study revealed that it cannot generate negative curvature by simply imposing its intrinsic curvature on the membrane. Introducing dynamics, we found that MIM IMD is actually considerably more flexible as compared to other BAR domains. Moreover, we discovered that MIM IMD can acquire a positive conformation, which may enable its suggested ability to sense and couple with positive membrane curvature. However, our study does not support the proposition that it would sense curvature via inserting its N-terminal amphipathic helix to a membrane. Additionally, our study reveals that significant protein-lipid interactions between the domain and lipids are driven by electrostatic interactions, which further induce clustering of phosphatidylinositol 4,5-biphosphate (PI(4,5)P2). We suggest the PI(4,5)P2-clustering may have a significant role in the curvature generation mechanism, due to increase of membrane fluidity.
So far MIM has been studied only experimentally. In this thesis, for the first time we employ molecular dynamics (MD) simulations to computationally address the membrane sculpting mechanism of MIM. We employ both atomistic and mesoscopic scale simulations, examining the behaviour of MIM IMD in the presence of lipid bilayers of different properties.
First, inspection of the crystal structure of the domain under study revealed that it cannot generate negative curvature by simply imposing its intrinsic curvature on the membrane. Introducing dynamics, we found that MIM IMD is actually considerably more flexible as compared to other BAR domains. Moreover, we discovered that MIM IMD can acquire a positive conformation, which may enable its suggested ability to sense and couple with positive membrane curvature. However, our study does not support the proposition that it would sense curvature via inserting its N-terminal amphipathic helix to a membrane. Additionally, our study reveals that significant protein-lipid interactions between the domain and lipids are driven by electrostatic interactions, which further induce clustering of phosphatidylinositol 4,5-biphosphate (PI(4,5)P2). We suggest the PI(4,5)P2-clustering may have a significant role in the curvature generation mechanism, due to increase of membrane fluidity.