Three large protein complexes known as ESCRT I, ESCRT II and ESCRT III drive the progression of ubiquitinated membrane cargo from early endosomes to lysosomes. Several steps in this process critically depend on PtdIns3P, the product of the class III phosphoinositide 3-kinase. Our work has provided insights into the architecture, membrane recruitment and functional interactions of the ESCRT machinery. The fan-shaped ESCRT I core and the trilobal ESCRT II core are essential to forming stable, rigid scaffolds that support additional, flexibly-linked domains, which serve as gripping tools for recognizing elements of the MVB (multivesicular body) pathway: cargo protein, membranes and other MVB proteins. With these additional (non-core) domains, ESCRT I grasps monoubiquitinated membrane proteins and the Vps36 subunit of the downstream ESCRT II complex. The GLUE (GRAM-like, ubiquitin-binding on Eap45) domain extending beyond the core of the ESCRT II complex recognizes PtdIns3P-containing membranes, monoubiquitinated cargo and ESCRT I. The structure of this GLUE domain demonstrates that it has a split PH (pleckstrin homology) domain fold, with a non-typical phosphoinositide-binding pocket. Mutations in the lipid-binding pocket of the ESCRT II GLUE domain cause a strong defect in vacuolar protein sorting in yeast.
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January 2007
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January 21 2007
Structural studies of phosphoinositide 3-kinase-dependent traffic to multivesicular bodies
David J. Gill;
David J. Gill
1
*MRC Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 2QH, U.K.
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Hsiangling Teo;
Hsiangling Teo
1
*MRC Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 2QH, U.K.
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Ji Sun;
Ji Sun
‡Department of Cellular and Molecular Medicine, The Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0668, U.S.A.
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Olga Perisic;
Olga Perisic
*MRC Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 2QH, U.K.
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Dmitry B. Veprintsev;
Dmitry B. Veprintsev
†Centre for Protein Engineering, Medical Research Council Centre, Cambridge, CB2 2QH, U.K.
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Yvonne Vallis;
Yvonne Vallis
*MRC Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 2QH, U.K.
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Scott D. Emr;
Scott D. Emr
‡Department of Cellular and Molecular Medicine, The Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0668, U.S.A.
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Roger L. Williams
Roger L. Williams
2
*MRC Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge, CB2 2QH, U.K.
2To whom correspondence should be addressed (email rlw@mrc-lmb.cam.ac.uk).
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Publisher: Portland Press Ltd
Online ISSN: 1744-1439
Print ISSN: 0067-8694
© 2006 Biochemical Society
2006
Biochem Soc Symp (2007) 74: 47–57.
Citation
Michael J.O. Wakelam, David J. Gill, Hsiangling Teo, Ji Sun, Olga Perisic, Dmitry B. Veprintsev, Yvonne Vallis, Scott D. Emr, Roger L. Williams; Structural studies of phosphoinositide 3-kinase-dependent traffic to multivesicular bodies. Biochem Soc Symp 12 January 2007; 74 47–57. doi: https://doi.org/10.1042/BSS2007c05
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