Lipid Scrambling Pathways in the Sec61 Translocon Complex
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388955%3A_____%2F25%3A00635761" target="_blank" >RIV/61388955:_____/25:00635761 - isvavai.cz</a>
Alternative codes found
RIV/00216224:14740/25:00141118 RIV/00216208:11310/25:10498974
Result on the web
<a href="https://hdl.handle.net/11104/0366788" target="_blank" >https://hdl.handle.net/11104/0366788</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/jacs.4c11142" target="_blank" >10.1021/jacs.4c11142</a>
Alternative languages
Result language
angličtina
Original language name
Lipid Scrambling Pathways in the Sec61 Translocon Complex
Original language description
Cellular homeostasis depends on the rapid, ATP-independent translocation of newly synthesized lipids across the endoplasmic reticulum (ER) membrane. Lipid translocation is facilitated by membrane proteins known as scramblases, a few of which have recently been identified in the ER. Our previous structure of the translocon-associated protein (TRAP) bound to the Sec61 translocation channel revealed local membrane thinning, suggesting that the Sec61/TRAP complex might be involved in lipid scrambling. Using complementary fluorescence spectroscopy assays, we detected nonselective scrambling by reconstituted translocon complexes. This activity was unaffected by Sec61 inhibitors that block its lateral gate, suggesting a second lipid scrambling pathway within the complex. Molecular dynamics simulations indicate that the trimeric TRAP subunit forms this alternative route, facilitating lipid translocation via a ´credit card´ mechanism, using a crevice lined with polar residues to shield lipid head groups from the hydrophobic membrane interior. Kinetic and thermodynamic analyses confirmed that local membrane thinning enhances scrambling efficiency and that both Sec61 and TRAP scramble phosphatidylcholine faster than phosphatidylethanolamine and phosphatidylserine, reflecting the intrinsic lipid flip-flop tendencies of these lipid species. As the Sec61 scrambling site lies in the lateral gate region, it is likely inaccessible during protein translocation, in line with our experiments on Sec61-inhibited samples. Hence, our findings suggest that the metazoan-specific trimeric TRAP bundle is a viable candidate for lipid scrambling activity that is insensitive to the functional state of the translocon.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10403 - Physical chemistry
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Journal of the American Chemical Society
ISSN
0002-7863
e-ISSN
1520-5126
Volume of the periodical
147
Issue of the periodical within the volume
19
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
15970-15984
UT code for WoS article
001482437300001
EID of the result in the Scopus database
2-s2.0-105004368151