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Sub-series 1: Angus & Robertson book reviews in bound volumes, 1894-1970

Arginine-rich cell-penetrating peptides do not enter cells by directly passing through a lipid membrane; they instead passively enter vesicles and live cells by inducing membrane multilamellarity and fusion. The molecular picture of this penetration mode, which differs qualitatively from the previously proposed direct mechanism, is provided by molecular dynamics simulations. The kinetics of vesicle agglomeration and fusion by an iconic cellpenetrating peptide—nonaarginine—are documented via real-time fluorescence techniques, while the induction of multilamellar phases in vesicles and live cells is demonstrated by a combination of electron and fluorescence microscopies. This concert of experiments and simulations reveals that the identified passive cell penetration mechanism bears analogy to vesicle fusion induced by calcium ions, indicating that the two processes may share a common mechanistic origin.

Proceedings of the National Academy of Sciences - PNAS, 2018-11, Vol.115 (47), p.11923-11928

Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore

Cryo-electron microscopy (cryo-EM) permits the determination of atomic protein structures by averaging large numbers of individual projection images recorded at cryogenic temperatures—a method termed single-particle analysis. The cryo-preservation traps proteins within a thin glass-like ice layer, making literally a freeze image of proteins in solution. Projections of randomly adopted orientations are merged to reconstruct a 3D density map. While atomic resolution for highly symmetric viruses was achieved already in 2009, the development of new sensitive and fast electron detectors has enabled cryo-EM for smaller and asymmetrical proteins including fragile membrane proteins. As one of the most important structural biology methods at present, cryo-EM was awarded in October 2017 with the Nobel Prize in Chemistry. The molecular understanding of Transient-Receptor-Potential (TRP) channels has been boosted tremendously by cryo-EM single-particle analysis. Several near-atomic and atomic structures gave important mechanistic insights, e.g., into ion permeation and selectivity, gating, as well as into the activation of this enigmatic and medically important membrane protein family by various chemical and physical stimuli. Lastly, these structures have set the starting point for the rational design of TRP channel-targeted therapeutics to counteract life-threatening channelopathies. Here, we attempt a brief introduction to the method, review the latest advances in cryo-EM structure determination of TRP channels, and discuss molecular insights into the channel function based on the wealth of TRP channel cryo-EM structures.

Pflügers Archiv, 2018-02, Vol.470 (2), p.213-225

Dawning of a new era in TRP channel structural biology by cryo-electron microscopy

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Sub-series 1: Angus & Robertson book reviews in bound volumes, 1894-1970

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Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore

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Dawning of a new era in TRP channel structural biology by cryo-electron microscopy

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Sub-series 1: Angus & Robertson book reviews in bound volumes, 1894-1970

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Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore

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Dawning of a new era in TRP channel structural biology by cryo-electron microscopy

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