Membrane invagination induced by Shiga toxin B-subunit: from molecular structure to tube formation
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Membrane invagination induced by Shiga toxin B-subunit : from molecular structure to tube formation. / Pezeshkian, W.; Hansen, A. G.; Johannes, L.; Khandelia, H.; Shillcock, J. C.; Kumar, P. B. S.; Ipsen, J. H.
I: Soft Matter, Bind 12, Nr. 23, 2016, s. 5164-5171.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Membrane invagination induced by Shiga toxin B-subunit
T2 - from molecular structure to tube formation
AU - Pezeshkian, W.
AU - Hansen, A. G.
AU - Johannes, L.
AU - Khandelia, H.
AU - Shillcock, J. C.
AU - Kumar, P. B. S.
AU - Ipsen, J. H.
PY - 2016
Y1 - 2016
N2 - The bacterial Shiga toxin is composed of an enzymatically active A-subunit, and a receptor-binding homopentameric B-subunit (STxB) that mediates intracellular toxin trafficking. Upon STxB-mediated binding to the glycolipid globotriaosylceramide (Gb(3)) at the plasma membrane of target cells, Shiga toxin is internalized by clathrin-dependent and independent endocytosis. The formation of tubular membrane invaginations is an essential step in the clathrin-independent STxB uptake process. However, the mechanism by which STxB induces these invaginations has remained unclear. Using a combination of all-atom molecular dynamics and Monte Carlo simulations we show that the molecular architecture of STxB enables the following sequence of events: the Gb(3) binding sites on STxB are arranged such that tight avidity-based binding results in a small increment of local curvature. Membrane-mediated clustering of several toxin molecules then creates a tubular membrane invagination that drives toxin entry into the cell. This mechanism requires: (1) a precise molecular architecture of the STxB binding sites; (2) a fluid bilayer in order for the tubular invagination to form. Although, STxB binding to the membrane requires specific interactions with Gb(3) lipids, our study points to a generic molecular design principle for clathrin-independent endocytosis of nanoparticles.
AB - The bacterial Shiga toxin is composed of an enzymatically active A-subunit, and a receptor-binding homopentameric B-subunit (STxB) that mediates intracellular toxin trafficking. Upon STxB-mediated binding to the glycolipid globotriaosylceramide (Gb(3)) at the plasma membrane of target cells, Shiga toxin is internalized by clathrin-dependent and independent endocytosis. The formation of tubular membrane invaginations is an essential step in the clathrin-independent STxB uptake process. However, the mechanism by which STxB induces these invaginations has remained unclear. Using a combination of all-atom molecular dynamics and Monte Carlo simulations we show that the molecular architecture of STxB enables the following sequence of events: the Gb(3) binding sites on STxB are arranged such that tight avidity-based binding results in a small increment of local curvature. Membrane-mediated clustering of several toxin molecules then creates a tubular membrane invagination that drives toxin entry into the cell. This mechanism requires: (1) a precise molecular architecture of the STxB binding sites; (2) a fluid bilayer in order for the tubular invagination to form. Although, STxB binding to the membrane requires specific interactions with Gb(3) lipids, our study points to a generic molecular design principle for clathrin-independent endocytosis of nanoparticles.
KW - FORCE-FIELD
KW - DYNAMICS
KW - CURVATURE
KW - GROMACS
KW - SCISSION
KW - SITES
KW - ENTRY
U2 - 10.1039/c6sm00464d
DO - 10.1039/c6sm00464d
M3 - Journal article
VL - 12
SP - 5164
EP - 5171
JO - Soft Matter
JF - Soft Matter
SN - 1744-683X
IS - 23
ER -
ID: 316868326