Membrane Thinning Induces Sorting of Lipids and the Amphipathic Lipid Packing Sensor (ALPS) Protein Motif

Hilten, Niek van; Stroh, Kai Steffen; Risselada, Herre Jelger

doi:10.3389/fphys.2020.00250

Cited by 25 publications

(48 citation statements)

References 59 publications

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“…For instance, in a complex ER-like membrane, we observed an average thinning of 26%, with fluctuations between 15-46%. As a consequence, the TM window seems enriched of lipids which usually form thin membranes (37) - especially unsaturated phosphatidylcholine lipids - which spread their acyl chains to squeeze into the window ( Fig. S14 ).…”

Section: Resultsmentioning

confidence: 99%

Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage

Liaci

Steigenberger

Tamara

et al. 2020

Preprint

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The signal peptidase complex (SPC) is an essential membrane complex in the endoplasmic reticulum (ER), where it removes signal peptides (SPs) from a large variety of secretory pre-proteins with exquisite specificity. Although the determinants of this process have been established empirically, the molecular details of SP recognition and removal remain elusive. Here, we show that the human SPC exists in two functional paralogs with distinct proteolytic subunits. We determined the atomic structures of both paralogs using electron cryo-microscopy and structural proteomics. The active site is formed by a catalytic triad and abuts the ER membrane, where a transmembrane window collectively formed by all subunits locally thins the bilayer. This unique architecture generates specificity for thousands of SPs based on the length of their hydrophobic segments.

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Section: Resultsmentioning

confidence: 99%

Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage

Liaci

Steigenberger

Tamara

et al. 2020

Preprint

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“…Indeed, the ALPS motif in the ATG14L BATS domain (Figure 2A,B) serves as a packing sensor of VPS34 complex I [26]. Packing defects can also be caused by membrane thinning in an artificial membrane system in which the ArfGAP1 ALPS motif is recruited to the thinned area [149]. A phospholipid is composed of a polar head comprising a modified alcohol (R) and a phosphate, a backbone (glycerol here, also can be sphingosine), and fatty acids or acyl chains.…”

Section: Lipid Packing Of Acyl Chainsmentioning

confidence: 99%

Section: Membrane Curvaturementioning

confidence: 99%

Activation Mechanisms of the VPS34 Complexes

Ohashi

2021

Cells

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Phosphatidylinositol-3-phosphate (PtdIns(3)P) is essential for cell survival, and its intracellular synthesis is spatially and temporally regulated. It has major roles in two distinctive cellular pathways, namely, the autophagy and endocytic pathways. PtdIns(3)P is synthesized from phosphatidylinositol (PtdIns) by PIK3C3C/VPS34 in mammals or Vps34 in yeast. Pathway-specific VPS34/Vps34 activity is the consequence of the enzyme being incorporated into two mutually exclusive complexes: complex I for autophagy, composed of VPS34/Vps34–Vps15/Vps15-Beclin 1/Vps30-ATG14L/Atg14 (mammals/yeast), and complex II for endocytic pathways, in which ATG14L/Atg14 is replaced with UVRAG/Vps38 (mammals/yeast). Because of its involvement in autophagy, defects in which are closely associated with human diseases such as cancer and neurodegenerative diseases, developing highly selective drugs that target specific VPS34/Vps34 complexes is an essential goal in the autophagy field. Recent studies on the activation mechanisms of VPS34/Vps34 complexes have revealed that a variety of factors, including conformational changes, lipid physicochemical parameters, upstream regulators, and downstream effectors, greatly influence the activity of these complexes. This review summarizes and highlights each of these influences as well as clarifying key questions remaining in the field and outlining future perspectives.

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“…The four membrane systems with the varying compositions are: 1) pure DOPC(dioleoyl-phosphatidylcholine), 2) DOPC:BSM(brain sphingomyelin):CHOL at a molar ratio of 4:4:2, 3) DOPC:BSM:CHOL:PIP2(Phosphatidylinositol bis-phosphate) at a molar ratio of 2:4:3:1, 4) myelin membrane DOPC:BSM:CHOL:PI(Phosphatidylinositol):DOPE:DOPS at a molar ratio of 4:3:1:1:0.4:0.6. The python script, insane.py, was used to generate each of the above mentioned membrane systems within a simulation box of 12 x 12 x 10 nm 3 solvated with explicit MARTINI water and with appropriate numbers of Na+ and Clcounter ions to make the charge of each of the system neutral (Van Hilten et al, 2020). After running a steepest descent minimization, a 200 ns NVT equilibration was executed with the temperature coupling by velocity rescaling thermostat to a reference temperature of 300K.…”

Section: Quantification Of Membrane Packing Defectsmentioning

confidence: 99%

In vitro reconstitution demonstrates the amyloid-beta mediated myelin membrane deformation

Tiwari

Pradhan

Sannigrahi

et al. 2021

Preprint

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Amyloid-beta (Ab) aggregation mediated neuronal membrane deformation, although poorly understood, is implicated in Alzheimer's Disease (AD). Particularly, whether Ab aggregation can induce neuronal demyelination remains unknown. Here we show that Aβ-40 binds and induces extensive tubulation in the myelin membrane in vitro. The binding of Aβ-40 depends predominantly on the lipid packing defect densities and electrostatic interactions and results in rigidification of the myelin membrane in the early time scales. Furthermore, elongation of Aβ-40 into higher oligomeric and fibrillar species leads to eventual fluidization of the myelin membrane followed by extensive membrane tubulation observed in the late phase. Taken together, our results capture mechanistic insights into snapshots of temporal dynamics of Aβ-40- myelin membrane interaction and demonstrate how short timescale, local phenomena of binding, and fibril mediated load generation manifests into long timescale, global phenomena of myelin tubulation and demonstrates the ability of Aβ-40 to demyelinate.

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Membrane Thinning Induces Sorting of Lipids and the Amphipathic Lipid Packing Sensor (ALPS) Protein Motif

Cited by 25 publications

References 59 publications

Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage

Structure of the Human Signal Peptidase Complex Reveals the Determinants for Signal Peptide Cleavage

Activation Mechanisms of the VPS34 Complexes

In vitro reconstitution demonstrates the amyloid-beta mediated myelin membrane deformation

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