Skip to main content
Log in

Self-assemblies of Rab- and Arf-family small GTPases on lipid bilayers in membrane tethering

  • Review
  • Published:
Biophysical Reviews Aims and scope Submit manuscript

Abstract

Small GTPases of the Ras superfamily, which include Ras-, Rho-, Rab-, Arf-, and Ran-family isoforms, are generally known to function as a nucleotide-dependent molecular switch in eukaryotic cells. In the GTP-loaded forms, they selectively recruit their cognate interacting proteins or protein complexes, termed “effectors,” to the cytoplasmic face of subcellular membrane compartments, thereby switching on the downstream effector functions, which are vital for fundamental cellular events, such as cell proliferation, cytoskeletal organization, and intracellular membrane trafficking. Nevertheless, in addition to acting as the classic nucleotide-dependent switches for the effectors, recent studies have uncovered that small GTPases themselves can be self-assembled specifically into homo-dimers or higher-order oligomers on membranes, and these assembly processes are likely responsible for their physiological functions. This Review focuses particularly on the self-assembly processes of Rab- and Arf-family isoforms during membrane tethering, the most critical step to ensure the fidelity of membrane trafficking. A summary of the current experimental evidence for self-assemblies of Rab and Arf small GTPases on lipid bilayers in chemically defined reconstitution system is provided

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abankwa D, Gorfe AA (2020) Mechanisms of Ras membrane organization and signaling: Ras rocks again. Biomolecules 10:1522

    Article  CAS  PubMed Central  Google Scholar 

  • Ainavarapu SR, Brujic J, Huang HH, Wiita AP, Lu H, Li L, Walther KA, Carrion-Vazquez M, Li H, Fernandez JM (2007) Contour length and refolding rate of a small protein controlled by engineered disulfide bonds. Biophys J 92:225–233

    Article  CAS  PubMed  Google Scholar 

  • Ali BR, Wasmeier C, Lamoreux L, Strom M, Seabra MC (2004) Multiple regions contribute to membrane targeting of Rab GTPases. J Cell Sci 117:6401–6412

    Article  CAS  PubMed  Google Scholar 

  • Beck R, Sun Z, Adolf F, Rutz C, Bassler J, Wild K, Sinning I, Hurt E, Brügger B, Béthune J, Wieland F (2008) Membrane curvature induced by Arf1-GTP is essential for vesicle formation. Proc Natl Acad Sci U S A 105:11731–11736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beck R, Prinz S, Diestelkötter-Bachert P, Röhling S, Adolf F, Hoehner K, Welsch S, Ronchi P, Brügger B, Briggs JA, Wieland F (2011) Coatomer and dimeric ADP ribosylation factor 1 promote distinct steps in membrane scission. J Cell Biol 194:765–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonifacino JS, Glick BS (2004) The mechanisms of vesicle budding and fusion. Cell 116:153–166

    Article  CAS  PubMed  Google Scholar 

  • Bourne HR, Sanders DA, McCormick F (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348:125–132

    Article  CAS  PubMed  Google Scholar 

  • Bremser M, Nickel W, Schweikert M, Ravazzola M, Amherdt M, Hughes CA, Söllner TH, Rothman JE, Wieland FT (1999) Coupling of coat assembly and vesicle budding to packaging of putative cargo receptors. Cell 96:495–506

    Article  CAS  PubMed  Google Scholar 

  • Cheung PY, Pfeffer SR (2016) Transport vesicle tethering at the trans golgi network: coiled coil proteins in action. Front Cell Dev Biol 4:18

    Article  PubMed  PubMed Central  Google Scholar 

  • Diestelkoetter-Bachert P, Beck R, Reckmann I, Hellwig A, Garcia-Saez A, Zelman-Hopf M, Hanke A, Nunes Alves A, Wade RC, Mayer MP, Wieland F (2020) Structural characterization of an Arf dimer interface: molecular mechanism of Arf-dependent membrane scission. FEBS Lett 594:2240–2253

    Article  CAS  PubMed  Google Scholar 

  • Donaldson JG, Jackson CL (2011) ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nat Rev Mol Cell Biol 12:362–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drin G, Morello V, Casella JF, Gounon P, Antonny B (2008) Asymmetric tethering of flat and curved lipid membranes by a golgin. Science 320:670–673

    Article  CAS  PubMed  Google Scholar 

  • D'Souza-Schorey C, Chavrier P (2006) ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol 7:347–358

    Article  CAS  PubMed  Google Scholar 

  • Erickson HP (2009) Size and shape of protein molecules at the nanometer level determined by sedimentation, gel filtration, and electron microscopy. Biol Proced Online 11:32–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujibayashi K, Mima J (2021) The small GTPase Arf6 functions as a membrane tether in a chemically-defined reconstitution system. Front Cell Dev Biol 9:628910

    Article  PubMed  PubMed Central  Google Scholar 

  • Gillingham AK, Munro S (2019) Transport carrier tethering - how vesicles are captured by organelles. Curr Opin Cell Biol 59:140–146

    Article  CAS  PubMed  Google Scholar 

  • Goitre L, Trapani E, Trabalzini L, Retta SF (2014) The Ras superfamily of small GTPases: the unlocked secrets. Methods Mol Biol 1120:1–18

    Article  CAS  PubMed  Google Scholar 

  • Grosshans BL, Ortiz D, Novick P (2006) Rabs and their effectors: achieving specificity in membrane traffic. Proc Natl Acad Sci U S A 103:11821–11827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heasman SJ, Ridley AJ (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat Rev Mol Cell Biol 9:690–701

    Article  CAS  PubMed  Google Scholar 

  • Hernandez JM, Kreutzberger AJ, Kiessling V, Tamm LK, Jahn R (2014) Variable cooperativity in SNARE-mediated membrane fusion. Proc Natl Acad Sci U S A 111:12037–12042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hutagalung AH, Novick PJ (2011) Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev 91:119–149

    Article  CAS  PubMed  Google Scholar 

  • Inoshita M, Mima J (2017) Human Rab small GTPase- and class V myosin-mediated membrane tethering in a chemically defined reconstitution system. J Biol Chem 292:18500–18517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson CL, Bouvet S (2014) Arfs at a glance. J Cell Sci 127:4103–4109

    CAS  PubMed  Google Scholar 

  • Ji H, Coleman J, Yang R, Melia TJ, Rothman JE, Tareste D (2010) Protein determinants of SNARE-mediated lipid mixing. Biophys J 99:553–560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karnoub AE, Weinberg RA (2008) Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9:517–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khatter D, Raina VB, Dwivedi D, Sindhwani A, Bahl S, Sharma M (2015) The small GTPase Arl8b regulates assembly of the mammalian HOPS complex on lysosomes. J Cell Sci 128:1746–1761

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klumperman J, Raposo G (2014) The complex ultrastructure of the endolysosomal system. Cold Spring Harb Perspect Biol 6:a016857

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuhlee A, Raunser S, Ungermann C (2015) Functional homologies in vesicle tethering. FEBS Lett 589:2487–2497

    Article  CAS  PubMed  Google Scholar 

  • Lee KY, Fang Z, Enomoto M, Gasmi-Seabrook G, Zheng L, Koide S, Ikura M, Marshall CB (2020) Two distinct structures of membrane-associated homodimers of GTP- and GDP-bound KRAS4B revealed by paramagnetic relaxation enhancement. Angew Chem Int Ed Eng 59:11037–11045

    Article  CAS  Google Scholar 

  • Li F, Yi L, Zhao L, Itzen A, Goody RS, Wu YW (2014) The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting. Proc Natl Acad Sci U S A 111:2572–2577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lo SY, Brett CL, Plemel RL, Vignali M, Fields S, Gonen T, Merz AJ (2012) Intrinsic tethering activity of endosomal Rab proteins. Nat Struct Mol Biol 19:40–47

    Article  CAS  Google Scholar 

  • Lu L, Hong W (2003) Interaction of Arl1-GTP with GRIP domains recruits autoantigens Golgin-97 and Golgin-245/p230 onto the Golgi. Mol Biol Cell 14:3767–3781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mima J (2018) Reconstitution of membrane tethering mediated by Rab-family small GTPases. Biophys Rev 10:543–549

    Article  CAS  PubMed  Google Scholar 

  • Muratcioglu S, Chavan TS, Freed BC, Jang H, Khavrutskii L, Freed RN, Dyba MA, Stefanisko K, Tarasov SG, Gursoy A, Keskin O, Tarasova NI, Gaponenko V, Nussinov R (2015) GTP-dependent K-Ras dimerization. Structure 23:1325–1335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagle JF, Tristram-Nagle S (2000) Structure of lipid bilayers. Biochim Biophys Acta 1469:159–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen N, Shteyn V, Melia TJ (2017) Sensing membrane curvature in macroautophagy. J Mol Biol 429:457–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Packer MR, Parker JA, Chung JK, Li Z, Lee YK, Cookis T, Guterres H, Alvarez S, Hossain MA, Donnelly DP, Agar JN, Makowski L, Buck M, Groves JT, Mattos C (2021) Raf promotes dimerization of the Ras G-domain with increased allosteric connections. Proc Natl Acad Sci U S A 118:e2015648118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paleotti O, Macia E, Luton F, Klein S, Partisani M, Chardin P, Kirchhausen T, Franco M (2005) The small G-protein Arf6GTP recruits the AP-2 adaptor complex to membranes. J Biol Chem 280:21661–21666

    Article  CAS  PubMed  Google Scholar 

  • Prakash P, Sayyed-Ahmad A, Cho KJ, Dolino DM, Chen W, Li H, Grant BJ, Hancock JF, Gorfe AA (2017) Computational and biochemical characterization of two partially overlapping interfaces and multiple weak-affinity K-Ras dimers. Sci Rep 7:40109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prigent M, Dubois T, Raposo G, Derrien V, Tenza D, Rossé C, Camonis J, Chavrier P (2003) ARF6 controls post-endocytic recycling through its downstream exocyst complex effector. J Cell Biol 163:1111–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rojas AM, Fuentes G, Rausell A, Valencia A (2012) The Ras protein superfamily: evolutionary tree and role of conserved amino acids. J Cell Biol 196:189–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosa-Ferreira C, Christis C, Torres IL, Munro S (2015) The small G protein Arl5 contributes to endosome-to-Golgi traffic by aiding the recruitment of the GARP complex to the Golgi. Biol Open 4:474–481

    Article  PubMed  PubMed Central  Google Scholar 

  • Segawa K, Tamura N, Mima J (2019) Homotypic and heterotypic trans-assembly of human Rab-family small GTPases in reconstituted membrane tethering. J Biol Chem 294:7722–7739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spang A (2016) Membrane tethering complexes in the endosomal system. Front Cell Dev Biol 4:35

    Article  PubMed  PubMed Central  Google Scholar 

  • Spang A, Matsuoka K, Hamamoto S, Schekman R, Orci L (1998) Coatomer, Arf1p, and nucleotide are required to bud coat protein complex I-coated vesicles from large synthetic liposomes. Proc Natl Acad Sci U S A 95:11199–11204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spencer-Smith R, Koide A, Zhou Y, Eguchi RR, Sha F, Gajwani P, Santana D, Gupta A, Jacobs M, Herrero-Garcia E, Cobbert J, Lavoie H, Smith M, Rajakulendran T, Dowdell E, Okur MN, Dementieva I, Sicheri F, Therrien M, Hancock JF, Ikura M, Koide S, O'Bryan JP (2017) Inhibition of RAS function through targeting an allosteric regulatory site. Nat Chem Biol 13:62–68

    Article  CAS  PubMed  Google Scholar 

  • Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10:513–525

    Article  CAS  PubMed  Google Scholar 

  • Sztul E, Chen PW, Casanova JE, Cherfils J, Dacks JB, Lambright DG, Lee FS, Randazzo PA, Santy LC, Schürmann A, Wilhelmi I, Yohe ME, Kahn RA (2019) ARF GTPases and their GEFs and GAPs: concepts and challenges. Mol Biol Cell 30:1249–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takamori S, Holt M, Stenius K, Lemke EA, Grønborg M, Riedel D, Urlaub H, Schenck S, Brügger B, Ringler P, Müller SA, Rammner B, Gräter F, Hub JS, De Groot BL, Mieskes G, Moriyama Y, Klingauf J, Grubmüller H, Heuser J, Wieland F, Jahn R (2006) Molecular anatomy of a trafficking organelle. Cell 127:831–846

    Article  CAS  PubMed  Google Scholar 

  • Tamura N, Mima J (2014) Membrane-anchored human Rab GTPases directly mediate membrane tethering in vitro. Biol Open 3:1108–1115

    Article  PubMed  PubMed Central  Google Scholar 

  • Ueda S, Tamura N, Mima J (2020) Membrane tethering potency of Rab-family small GTPases is defined by the C-terminal hypervariable regions. Front Cell Dev Biol 8:577342

    Article  PubMed  PubMed Central  Google Scholar 

  • van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van QN, Prakash P, Shrestha R, Balius TE, Turbyville TJ, Stephen AG (2021) RAS nanoclusters: dynamic signaling platforms amenable to therapeutic intervention. Biomolecules 11:377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vance JE (2015) Phospholipid synthesis and transport in mammalian cells. Traffic 16:1–18

    Article  CAS  PubMed  Google Scholar 

  • Waters MG, Pfeffer SR (1999) Membrane tethering in intracellular transport. Curr Opin Cell Biol 11:453–459

    Article  CAS  PubMed  Google Scholar 

  • Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Lee M, Fairn GD (2018) Phospholipid subcellular localization and dynamics. J Biol Chem 293:6230–6240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu IM, Hughson FM (2010) Tethering factors as organizers of intracellular vesicular traffic. Annu Rev Cell Dev Biol 26:137–156

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Prakash P, Gorfe AA, Hancock JF (2018) Ras and the plasma membrane: a complicated relationship. Cold Spring Harb Perspect Med 8:a031831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zick M, Stroupe C, Orr A, Douville D, Wickner WT (2014) Membranes linked by trans-SNARE complexes require lipids prone to non-bilayer structure for progression to fusion. eLife 3:e01879

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joji Mima.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mima, J. Self-assemblies of Rab- and Arf-family small GTPases on lipid bilayers in membrane tethering. Biophys Rev 13, 531–539 (2021). https://doi.org/10.1007/s12551-021-00819-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12551-021-00819-4

Keywords

Navigation