Rhomboid-catalyzed intramembrane proteolysis requires hydrophobic matching with the surrounding lipid bilayer

Engberg, Oskar; Ulbricht, David; Döbel, Viola; Siebert, Verena; Frie, Christian; Penk, Anja; Lemberg, Marius K.; Huster, Daniel

doi:10.1126/sciadv.abq8303

Cited by 18 publications

(20 citation statements)

References 48 publications

(78 reference statements)

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“…Serotonin appears to enter deeper into the POPC membrane, and the tilt angle of serotonin with respect to the membrane normal appears to be higher for POPC compared to POPS (Figure A,B). The lipid water interface of a biological membrane is a highly specialized and complex molecular assembly where various physical interactions contribute to the packing and lateral organization of the molecules constituting this layer. − Accordingly, the localization of a small molecule in this broad interface is subject to a complicated balance of forces which results in the specific orientation and average localization of the respected molecule that is described by a minimum in the free energy. − These interactions determine the impact of the small molecule on the surrounding lipids. Physical forces that contribute to this free energy include Coulomb, charge–dipole, dipole–dipole, and cation–pi (π), interactions.…”

Section: Discussionmentioning

confidence: 99%

Unusual Robustness of Neurotransmitter Vesicle Membranes against Serotonin-Induced Perturbations

et al. 2023

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Nature confines hundreds of millimolar of amphiphilic neurotransmitters, such as serotonin, in synaptic vesicles. This appears to be a puzzle, as the mechanical properties of lipid bilayer membranes of individual major polar lipid constituents of synaptic vesicles [phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS)] are significantly affected by serotonin, sometimes even at few millimolar concentrations. These properties are measured by atomic force microscopy, and their results are corroborated by molecular dynamics simulations. Complementary 2H solid-state NMR measurements also show that the lipid acyl chain order parameters are strongly affected by serotonin. The resolution of the puzzle lies in the remarkably different properties displayed by the mixture of these lipids, at molar ratios mimicking those of natural vesicles (PC:PE:PS:Cholesterol = 3:5:2:5). Bilayers constituting of these lipids are minimally perturbed by serotonin, and show only a graded response at physiological concentrations (>100 mM). Significantly, the cholesterol (up to 33% molar ratio) plays only a minor role in dictating these mechanical perturbations, with PC:PE:PS:Cholesterol = 3:5:2:5 and 3:5:2:0 showing similar perturbations. We infer that nature uses an emergent mechanical property of a specific mixture of lipids, all individually vulnerable to serotonin, to appropriately respond to physiological serotonin levels.

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Section: Discussionmentioning

confidence: 99%

Unusual Robustness of Neurotransmitter Vesicle Membranes against Serotonin-Induced Perturbations

et al. 2023

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“…MPs isolated from cellular membranes are likely to lose activity and native conformation required for functional analyses and structural studies. − Structural characterization of MPs in native cellular membranes provides valuable insights into their molecular mechanisms within the functional context. In situ studies offer several advantages over in vitro studies conducted in membrane mimic environments.…”

Section: Discussionmentioning

confidence: 99%

Membrane Protein Structures in Native Cellular Membranes Revealed by Solid-State NMR Spectroscopy

Zhang,

Gan,

Zhao

et al. 2023

JACS Au

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The structural characterization of membrane proteins within the cellular membrane environment is critical for understanding the molecular mechanism in their native functional context. However, conducting residue site-specific structural analysis of membrane proteins in native membranes by solid-state NMR faces challenges due to poor spectral sensitivity and serious interference from background protein signals. In this study, we present a new protocol that combines various strategies for cellular membrane sample preparations, enabling us to reveal the secondary structure of the mechanosensitive channel of large conductance from Methanosarcina acetivorans ( Ma MscL) in Escherichia coli inner membranes. Our findings demonstrate the feasibility of achieving complete resonance assignments and the potential for determining the 3D structures of membrane proteins within cellular membranes. We find that the use of the BL21(DE3) strain in this protocol is crucial for effectively suppressing background protein labeling without compromising the sensitivity of the target protein. Furthermore, our data reveal that the structures of different proteins exhibit varying degrees of sensitivity to the membrane environment. These results underscore the significance of studying membrane proteins within their native cellular membranes when performing structural characterizations. Overall, this study opens up a new avenue for achieving the atomic-resolution structural characterization of membrane proteins within their native cellular membranes, providing valuable insights into the nativeness of membrane proteins.

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“…This study is the first to demonstrate chaperone-like activity for any rhomboid protein. Many rhomboid proteins use similar functions to Dfm1 to promote retrotranslocation, and the rhomboid protease RHBDL4 has recently been characterized as acting on aggregation-prone substrates [19,28,[35][36][37]. It will be an interesting and important further line of inquiry to determine if a chaperone-like activity is a common ability of rhomboid proteins, both for the pseudoproteases and proteases.…”

Section: Introductionmentioning

confidence: 99%

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

et al. 2023

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Protein aggregates are a common feature of diseased and aged cells. Membrane proteins comprise a quarter of the proteome, and yet, it is not well understood how aggregation of membrane proteins is regulated and what effects these aggregates can have on cellular health. We have determined in yeast that the derlin Dfm1 has a chaperone-like activity that influences misfolded membrane protein aggregation. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1’s previously identified function in dislocating misfolded membrane proteins from the endoplasmic reticulum (ER) to the cytosol for degradation. Additionally, we assess the cellular impacts of misfolded membrane proteins in the absence of Dfm1 and determine that misfolded membrane proteins are toxic to cells in the absence of Dfm1 and cause disruptions to proteasomal and ubiquitin homeostasis.

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Rhomboid-catalyzed intramembrane proteolysis requires hydrophobic matching with the surrounding lipid bilayer

Cited by 18 publications

References 48 publications

Unusual Robustness of Neurotransmitter Vesicle Membranes against Serotonin-Induced Perturbations

Unusual Robustness of Neurotransmitter Vesicle Membranes against Serotonin-Induced Perturbations

Membrane Protein Structures in Native Cellular Membranes Revealed by Solid-State NMR Spectroscopy

Yeast derlin Dfm1 employs a chaperone-like function to resolve misfolded membrane protein stress

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