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          Institute: MPI für Entwicklungsbiologie     Collection: Abteilung 1 - Protein Evolution (A. Lupas)     Display Documents

ID: 732959.0, MPI für Entwicklungsbiologie / Abteilung 1 - Protein Evolution (A. Lupas)
An endosomal tether undergoes an entropic collapse to bring vesicles together
Authors:Murray, D. H.; Jahnel, M.; Lauer, J.; Avellaneda, M. J.; Brouilly, N.; Cezanne, A.; Morales-Navarrete, H.; Perini, E. D.; Ferguson, C.; Lupas, A. N.; Kalaidzidis, Y.; Parton, R. G.; Grill, S. W.; Zerial, M.
Date of Publication (YYYY-MM-DD):2016-09-01
Title of Journal:Nature
Issue / Number:7618
Start Page:107
End Page:111
Review Status:Internal review
Audience:Not Specified
Abstract / Description:An early step in intracellular transport is the selective recognition of a vesicle by its appropriate target membrane, a process regulated by Rab GTPases via the recruitment of tethering effectors. Membrane tethering confers higher selectivity and efficiency to membrane fusion than the pairing of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) alone. Here we address the mechanism whereby a tethered vesicle comes closer towards its target membrane for fusion by reconstituting an endosomal asymmetric tethering machinery consisting of the dimeric coiled-coil protein EEA1 (refs 6, 7) recruited to phosphatidylinositol 3-phosphate membranes and binding vesicles harbouring Rab5. Surprisingly, structural analysis reveals that Rab5:GTP induces an allosteric conformational change in EEA1, from extended to flexible and collapsed. Through dynamic analysis by optical tweezers, we confirm that EEA1 captures a vesicle at a distance corresponding to its extended conformation, and directly measure its flexibility and the forces induced during the tethering reaction. Expression of engineered EEA1 variants defective in the conformational change induce prominent clusters of tethered vesicles in vivo. Our results suggest a new mechanism in which Rab5 induces a change in flexibility of EEA1, generating an entropic collapse force that pulls the captured vesicle towards the target membrane to initiate docking and fusion.
Free Keywords:Allosteric Regulation; Endosomes/*metabolism; *Entropy; Guanosine Triphosphate/metabolism; Humans; *Membrane Fusion; Optical Tweezers; Phosphatidylinositol Phosphates/metabolism; Pliability; Protein Binding; Protein Conformation; SNARE Proteins/metabolism; Vesicular Transport Proteins/*chemistry/genetics/*metabolism; rab5 GTP-Binding Proteins/*metabolism
External Publication Status:published
Document Type:Article
Affiliations:MPI für Entwicklungsbiologie/Abteilung 1 - Proteinevolution (Andrei Lupas)
MPI für molekulare Zellbiologie und Genetik
External Affiliations:Biotechnology Center, Technical University Dresden, Tatzberg 47/49, 01307 Dresden, Germany. Max Planck Institute for the Physics of Complex Systems, Nothnitzerstrasse 38, 01187 Dresden, Germany. Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia. Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, 72076 Tubingen, Germany. Centre for Microscopy and Microanalysis, The University of Queensland, St Lucia 4072, Australia.
Identifiers:ISSN:1476-4687 (Electronic) 0028-0836 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/27556945 [ID No:2]
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