Dissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level

Lijun Shi, Chenguang Yang, Mingyuan Zhang, Kangning Li, Keying Wang, Li Jiao, Ruming Liu, Yunyun Wang, Ming Li, Yong Wang (), Lu Ma (), Shuxin Hu () and Xin Bian ()
Additional contact information
Lijun Shi: Nankai University
Chenguang Yang: Chinese Academy of Sciences
Mingyuan Zhang: Zhejiang University
Kangning Li: Nankai University
Keying Wang: Zhejiang University
Li Jiao: Nankai University
Ruming Liu: Nankai University
Yunyun Wang: Nankai University
Ming Li: Chinese Academy of Sciences
Yong Wang: Zhejiang University
Lu Ma: Chinese Academy of Sciences
Shuxin Hu: Chinese Academy of Sciences
Xin Bian: Nankai University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Homotypic membrane fusion of the endoplasmic reticulum (ER) is mediated by dynamin-like GTPase atlastin (ATL). This fundamental process relies on GTP-dependent domain rearrangements in the N-terminal region of ATL (ATLcyto), including the GTPase domain and three-helix bundle (3HB). However, its conformational dynamics during the GTPase cycle remain elusive. Here, we combine single-molecule FRET imaging and molecular dynamics simulations to address this conundrum. Different from the prevailing model, ATLcyto can form a loose crossover dimer upon GTP binding, which is tightened by GTP hydrolysis for membrane fusion. Furthermore, the α-helical motif between the 3HB and transmembrane domain, which is embedded in the surface of the lipid bilayer and self-associates in the crossover dimer, is required for ATL function. To recycle the proteins, Pi release, which disassembles the dimer, activates frequent relative movements between the GTPase domain and 3HB, and subsequent GDP dissociation alters the conformational preference of the ATLcyto monomer for entering the next reaction cycle. Finally, we found that two disease-causing mutations affect human ATL1 activity by destabilizing GTP binding-induced loose crossover dimer formation and the membrane-embedded helix, respectively. These results provide insights into ATL-mediated homotypic membrane fusion and the pathological mechanisms of related disease.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46919-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46919-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46919-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().