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PreprintCited by 12Cellular transport and secretionAdvanced Electron Microscopy Techniques and ApplicationsProtein Structure and Dynamics

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Structure of full-length ERGIC-53 in complex with MCFD2 for cargo transport

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Watanabe, Satoshi, Kise, Yoshiaki, Yonezawa, Kento, Inoue, Mariko, Shimizu, Nobutaka, Nureki, Osamu, Inaba, Kenji·2023·Nature Communications
DOI 10.1101/2023.08.27.554937PMC PMC10944485

Preprint — published as 10.1038/s41467-024-46747-1 · Paper page

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Abstract

ERGIC-53 is a cargo receptor that promotes the transport of certain subsets of newly synthesized secretory proteins and membrane proteins from the endoplasmic reticulum (ER) to the Golgi apparatus (GA) 1,2 . Despite numerous structural and functional studies since its identification, the overall architecture and mechanism of action of this cargo receptor in its full-length form remain unclear. Here we present cryo-electron microscopy (cryo-EM) structures of full-length ERGIC-53 in complex with its functional partner MCFD2. These structures, in combination with SEC-MALS/SAXS analysis, reveal that ERGIC-53 exists as a homotetramer, not a homohexamer as previously suggested, and comprises a four-leaf clover-like head structure and a long stalk composed of three sets of four-helix coiled-coil followed by a transmembrane (TM) domain. The tetrameric head of ERGIC-53 consists of the vertically assembled carbohydrate recognition domains and the central four-helix coiled-coil. 3D variability analysis visualizes the globally flexible motion of the long stalk and local plasticity of the head region. Notably, MCFD2 has been found to possess a Zn 2+ binding site in its N-terminal lid, which appears to modulate cargo binding. Altogether, unique mechanisms of regulated cargo capture and release by ERGIC-53 via the stalk bending and metal binding are proposed.

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Metadata

Authors
Watanabe, S., Kise, Y., Yonezawa, K., Inoue, M., Shimizu, N., Nureki, O., & Inaba, K.
Affiliations
  • Tohoku University (JP)
  • The University of Tokyo (JP)
  • High Energy Accelerator Research Organization (JP)
  • Kyushu University (JP)
Corresponding author
  • Watanabe, Satoshi
  • Inaba, Kenji
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2023-08-27
Volume
15
Issue
1
Pages
2404-2404
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2023.08.27.554937
PMC
PMC10944485
OpenAlex
W4392878896
Cited by
12
References
1
Citations by year
2026: 5 · 2025: 6 · 2024: 1
FWCI
2.68
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders
  • Naito Foundation
  • Japan Agency for Medical Research and Development (JP21am0101071, CREST, JP21am0101115, JP22gm6410026, JP21am0101095, 21gm1410006h0001, JP23ama121012, JP23ama121038)
  • Ministry of Education, Culture, Sports, Science and Technology (JP18K06075,JP21H05253, JP23K18193, JP21H05253, JP23K18193, JP18K06075, CREST)
  • Mochida Memorial Foundation for Medical and Pharmaceutical Research
  • Japan Society for the Promotion of Science (19H05781, 21H04758, 22K19263, 23K23819, 18K06075, CREST, 23K18193)
  • Core Research for Evolutional Science and Technology (21gm1410006h0001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
ERGIC-53, MCFD2, homotetramer, freight transport, secretory protein transport, Golgi apparatus, endoplasmic reticulum, transmembrane domain, cargo binding, cargo release, protein structure
MeSH terms
Binding Sites, Golgi Apparatus, Membrane Proteins, Protein Binding, Vesicular Transport Proteins, Mannose-Binding Lectins

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