Membrane Biology

Membrane Position of Ibuprofen Agrees with Suggested Access Path Entrance to Cytochrome P450 2C9 Active Site

by Karel Berka

GRP78: a chaperone with diverse roles beyond the endoplasmic reticulum.

by Gustaaf de Ridder

SALYAEV, R. K., CHERNYSHOV, V. I., KUZEVANOV, V. Y. Membrane biogenesis on isolated protoplasma surface. In: in: Proc. 9th Inter. Congr. on Electron Microscopy, Toronto, 1978

by Victor Kuzevanov

Salyaev R.K., Kuzevanov V.Ya, Khaptagaev S.B., Kopytchuk V.N. Isolation and purification of vacuoles and vacuolar membranes of plant cells. Fiziologiya rasteniy (Russian Plant Physiology).-1981.- v. 2, No 6. - P. 1295-1305 (in Russian).

by Victor Kuzevanov

Kuzevanov V.Ya., Katkov B.B., Salyaev R.K. General principles of isolation of vacuoles and vacuolar membranes. In: Structure and function of biological membranes of plants. - Novosibirsk: Nauka, 1985. - P.93-107 (in Russian)

by Victor Kuzevanov

Perturbations of model membranes induced by pathogenic dynorphin A mutants causing neurodegeneration in human brain

by sebastian wärmländer

The Role of the Disulfide Bond In the Interaction of Islet Amyloid Polypeptide With Membranes

by Maarten Engel

Khemtémourian, L., M. Engel, J. Kruijtzer, J. Höppener, R. Liskamp and J. Killian, European Biophysics Journal, 2010. 39: p. 1359-1364.

Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes... more Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes mellitus. It has been suggested that the N-terminal part, which contains a conserved intramolecular disulfide bond between residues 2 and 7, interacts with membranes, ultimately leading to membrane damage and b-cell death. Here, we used variants of the hIAPP1–19 fragment and model membranes of phosphatidylcholine and phosphatidylserine (7:3, molar ratio) to examine the role of this disulfide in membrane interactions. We found that the disulfide bond has a minor effect on membrane insertion properties and peptide conformational behavior, as studied by monolayer techniques, 2H NMR, ThT-fluorescence, membrane leakage, and CD spectroscopy. The results suggest that the disulfide bond does not play a significant role in hIAPP–membrane interactions. Hence, the fact that this bond is conserved is most likely related exclusively to the biological activity of IAPP as a hormone.

The N-Terminal Fragment of Human Islet Amyloid PolyPeptide is Non-Fibrillogenic In the Presence of Membranes and Does Not Cause Leakage of Bilayers of …

by Maarten Engel

Khemtémourian, L., M.F.M. Engel, R.M.J. Liskamp, J.W.M. Höppener and J.A. Killian, Biochimica et Biophysica Acta (BBA) - Biomembranes, 2010. 1798: p. 1805–1811.

Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes... more Human islet amyloid polypeptide (hIAPP) forms amyloid fibrils in pancreatic islets of patients with type 2 diabetes mellitus (DM2). The formation of hIAPP fibrils has been shown to cause membrane damage which most likely is responsible for the death of pancreatic islet β-cells during the pathogenesis of DM2. Previous studies have shown that the N-terminal part of hIAPP, hIAPP1–19, plays a major role in the initial interaction of hIAPP with lipid membranes. However, the exact role of this N-terminal part of hIAPP in causing membrane damage is unknown. Here we investigate the structure and aggregation properties of hIAPP1–19 in relation to membrane damage in vitro by using membranes of the zwitterionic lipid phosphatidylcholine (PC), the anionic lipid phosphatidylserine (PS) and mixtures of these lipids to mimic membranes of islet cells. Our data reveal that hIAPP1–19 is weakly fibrillogenic in solution and not fibrillogenic in the presence of membranes, where it adopts a secondary structure that is dependent on lipid composition and stable in time. Furthermore, hIAPP1–19 is not able to induce leakage in membranes of PC/PS or PC bilayers, indicating that the membrane interaction of the N-terminal fragment by itself is not responsible for membrane leakage under physiologically relevant conditions. In bilayers of the anionic lipid PS, the peptide does induce membrane damage, but this leakage is not correlated to fibril formation, as it is for mature hIAPP. Hence, membrane permeabilization by the N-terminal fragment of hIAPP in anionic lipids is most likely an aspecific process, occurring via a mechanism that is not relevant for hIAPP-induced membrane damage in vivo.

Membrane Damage by Human Islet Amyloid Polypeptide Through Fibril Growth at the Membrane

by Maarten Engel

Engel, M.F.M., L. Khemtémourian, C.C. Kleijer, H.J.D. Meeldijk, J. Jacobs, A.J. Verkleij, B. de Kruijff, J.A. Killian and J.W.M. Höppener, Proceedings of the National Academy of Sciences of the United States of America, 2008. 105(16): p. 6033-6038.

Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the... more Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulin-producing islet
cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this
cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional
mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.

Islet Amyloid Polypeptide-Induced Membrane Leakage Involves Uptake of Lipids by Forming Amyloid Fibers

by Maarten Engel

Engel, M.F.M., Sparr, E., de Kruijff, B., Höppener, J.W.M. & Killian, J.A. (2005) Biophys J 88(1):422A-422A.

Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic... more Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence
confocal microscopy on lipid vesicles that the process of hIAPP
amyloid formation is accompanied by a loss of barrier function,
whereby lipids are extracted from the membrane and taken up in
the forming amyloid deposits. No membrane interaction was
observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins.

Primary Human CD4+ T cells have diverse levels of membrane lipid order that correlate with their function.

by Chrissie Lim

2nd Co-author: Miguel L, Owen DM, [Lim C], Liebig C, Evans J, Magee AI and Jury EC.
In press, the Journal of Immunology. (Accepted for publication, December 2010.)