ESCRT-I Core and ESCRT-II GLUE Domain Structures Reveal Role for GLUE in Linking to ESCRT-I and Membranes
Open accessAbstract
ESCRT complexes form the main machinery driving protein sorting from endosomes to lysosomes. Currently, the picture regarding assembly of ESCRTs on endosomes is incomplete. The structure of the conserved heterotrimeric ESCRT-I core presented here shows a fan-like arrangement of three helical hairpins, each corresponding to a different subunit. Vps23/Tsg101 is the central hairpin sandwiched between the other subunits, explaining the critical role of its "steadiness box" in the stability of ESCRT-I. We show that yeast ESCRT-I links directly to ESCRT-II, through a tight interaction of Vps28 (ESCRT-I) with the yeast-specific zinc-finger insertion within the GLUE domain of Vps36 (ESCRT-II). The crystal structure of the GLUE domain missing this insertion reveals it is a split PH domain, with a noncanonical lipid binding pocket that binds PtdIns3P. The simultaneous and reinforcing interactions of ESCRT-II GLUE domain with membranes, ESCRT-I, and ubiquitin are critical for ubiquitinated cargo progression from early to late endosomes.
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Both crystals are composed of helical assemblies of hetero-tetramer ESCRT-I complexes, and human VPS28-TSG101 subcomplex forms filaments in solution.
“both crystals are composed of helical assemblies of the hetero-tetramer ESCRT-I complexes and a human VPS28-TSG101 subcomplex was shown to form filaments in solution as verified by negative stain electron microscopy [30,32].”
From Budding of a Retrovirus: Some Assemblies Required (2020) · cites this paper as [30]
The functional human ESCRT-I complex is a hetero-tetramer of VPS28, TSG101, VPS37, and MVB12.
“the functional ESCRT-I complex in humans organizes itself as a hetero-tetramer composed of a single copy of VPS28, TSG101, VPS37, and MVB12.”
From Budding of a Retrovirus: Some Assemblies Required (2020) · cites this paper as [30]
The ESCRT-I complex has a globular head with descending alpha helical hairpins, VPS28 top, VPS37 bottom, and a coiled-coil stalk.
“The complex assumes the structure of a globular head that is oriented as a descending stack of alpha helical hairpins with VPS28 on the top and VPS37 on the bottom, with a protruding coiled-coil stalk [29,30,31,32].”
From Budding of a Retrovirus: Some Assemblies Required (2020) · cites this paper as [30]
The 54EKAYIKD60 motif in human VPS28 is essential for forming helical assemblies.
“a highly conserved motif 54EKAYIKD60 located at the start of the alpha helical hairpin in the N-terminus of human VPS28 was essential for forming helical assemblies”
From Budding of a Retrovirus: Some Assemblies Required (2020) · cites this paper as [30]
Human ESCRT-I complex solved via crystallography bore striking similarity to the homologous complex in yeast.
“the human ESCRT-I complex was solved via crystallography and bore striking similarity to the homologous complex in yeast.”
From Budding of a Retrovirus: Some Assemblies Required (2020) · cites this paper as [30]
Contacts between neighboring VPS28 molecules are essential for higher-order assembly in yeast and human ESCRT-I filaments.
“in both yeast and human ESCRT-I filaments, it appeared that contacts between neighboring VPS28 molecules were essential for higher-order assembly”
From Budding of a Retrovirus: Some Assemblies Required (2020) · cites this paper as [30]
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Background
- Authors
- Teo, H., Gill, D. J., Sun, J., Perisic, O., Veprintsev, D. B., Vallis, Y., Emr, S. D., & Williams, R. L.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Howard Hughes Medical Institute (US)
- Medical Research Council (GB)
- Corresponding author
- Teo, Hsiangling
- Williams, Roger L.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-04
- Volume
- 125
- Issue
- 1
- Pages
- 99-111
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2136605585
- Cited by
- 242
- References
- 3
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 6 · 2021: 10 · 2020: 16 · 2019: 12 · 2018: 7 · 2017: 4 · 2016: 8 · 2015: 6 · 2014: 11 · 2013: 13 · 2012: 17
- FWCI
- 9.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2664 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- ESCRT-I, ESCRT-II, VPS36, VPS28, protein complex formation, endosomal sorting, lysosomal biogenesis, pleckstrin homology domain, ubiquitin, membrane binding, crystal structure
- MeSH terms
- Amino Acid Sequence, Carrier Proteins, Chromatography, Gel, Intracellular Membranes, Lipids, Liposomes, Lysosomes, Models, Biological, Models, Molecular, Molecular Sequence Data, Protein Binding, Endosomes, Saccharomyces cerevisiae, Protein Structure, Secondary, Protein Structure, Tertiary, Phosphatidylinositol Phosphates, Crystallography, X-Ray, Protein Transport, Transport Vesicles, Ubiquitin, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins, Multiprotein Complexes, Endosomal Sorting Complexes Required for Transport
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