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PreprintCited by 63Lipid Membrane Structure and BehaviorCellular transport and secretionLipid metabolism and biosynthesis

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Lipid scrambling is a general feature of protein insertases

Open access
Li, Dazhi, Rocha-Roa, Cristian, Schilling, Matthew A., Reinisch, Karin M., Vanni, Stefano·2023·Proceedings of the National Academy of Sciences
DOI 10.1101/2023.09.01.555937PMC PMC11047089

Preprint — published as 10.1073/pnas.2319476121 · Paper page

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Abstract

Glycerophospholipids are synthesized primarily in the cytosolic leaflet of the endoplasmic reticulum (ER) membrane and must be equilibrated between bilayer leaflets to allow the ER and membranes derived from it to grow. Lipid equilibration is facilitated by integral membrane proteins called “scramblases”. These proteins feature a hydrophilic groove allowing the polar heads of lipids to traverse the hydrophobic membrane interior, similar to a credit-card moving through a reader. Nevertheless, despite their fundamental role in membrane expansion and dynamics, the identity of most scramblases has remained elusive. Here, combining biochemical reconstitution and molecular dynamics simulations, we show that lipid scrambling is a general feature of protein insertases, integral membrane proteins which insert polypeptide chains into membranes of the ER and organelles disconnected from vesicle trafficking. Our data indicate that lipid scrambling occurs in the same hydrophilic channel through which protein insertion takes place, and that scrambling is abolished in the presence of nascent polypeptide chains. We propose that protein insertases could have a so-far overlooked role in membrane dynamics as scramblases.

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Metadata

Authors
Li, D., Rocha-Roa, C., Schilling, M. A., Reinisch, K. M., & Vanni, S.
Affiliations
  • Yale University (US)
  • University of Fribourg (CH)
Corresponding author
  • Li, Dazhi
  • Reinisch, Karin M.
  • Vanni, Stefano
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
openRxiv
Published
2023-09-01
Volume
121
Issue
17
Pages
e2319476121-e2319476121
ISSN
0027-8424 (ISSN-L)
DOI
10.1101/2023.09.01.555937
PMC
PMC11047089
OpenAlex
W4394804004
Cited by
63
References
1
Citations by year
2026: 15 · 2025: 33 · 2024: 9 · 2023: 6
FWCI
7.76
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • European Commission (803952, HORIZON2020)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (189996)
  • China Scholarship Council
  • Centro Svizzero di Calcolo Scientifico (s1176, s1030, s1221, s1176 s1030 s1221)
  • National Supercomputing Centre Singapore
  • National Institute of General Medical Sciences (R35GM131715)
  • HORIZON EUROPE European Research Council (803952)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
lipid scrambling, scramblase, glycerophospholipids, endoplasmic reticulum membrane, integral membrane proteins, hydrophilic channels, nascent polypeptide chains, membrane dynamics, protein insertion

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