Structure of a TRAPPII-Rab11 Activation Intermediate Reveals GTPase Substrate Selection Mechanisms

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 May 13

PMID 35559680

Authors

Saket R Bagde

J Christopher Fromme

Affiliations

Soon will be listed here.

Abstract

Rab1 and Rab11 are essential regulators of the eukaryotic secretory and endocytic recycling pathways. The transport protein particle (TRAPP) complexes activate these guanosine triphosphatases via nucleotide exchange using a shared set of core subunits. The basal specificity of the TRAPP core is toward Rab1, yet the TRAPPII complex is specific for Rab11. A steric gating mechanism has been proposed to explain TRAPPII counterselection against Rab1. Here, we present cryo-electron microscopy structures of the 22-subunit TRAPPII complex from budding yeast, including a TRAPPII-Rab11 nucleotide exchange intermediate. The Trs130 subunit provides a "leg" that positions the active site distal to the membrane surface, and this leg is required for steric gating. The related TRAPPIII complex is unable to activate Rab11 because of a repulsive interaction, which TRAPPII surmounts using the Trs120 subunit as a "lid" to enclose the active site. TRAPPII also adopts an open conformation enabling Rab11 to access and exit from the active site chamber.

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References

Yip C, Berscheminski J, Walz T . Molecular architecture of the TRAPPII complex and implications for vesicle tethering. Nat Struct Mol Biol. 2010; 17(11):1298-304. PMC: 2988884. DOI: 10.1038/nsmb.1914. View

Zivanov J, Nakane T, Scheres S . Estimation of high-order aberrations and anisotropic magnification from cryo-EM data sets in -3.1. IUCrJ. 2020; 7(Pt 2):253-267. PMC: 7055373. DOI: 10.1107/S2052252520000081. View

Rak A, Pylypenko O, Niculae A, Pyatkov K, Goody R, Alexandrov K . Structure of the Rab7:REP-1 complex: insights into the mechanism of Rab prenylation and choroideremia disease. Cell. 2004; 117(6):749-60. DOI: 10.1016/j.cell.2004.05.017. View

Cai Y, Chin H, Lazarova D, Menon S, Fu C, Cai H . The structural basis for activation of the Rab Ypt1p by the TRAPP membrane-tethering complexes. Cell. 2008; 133(7):1202-13. PMC: 2465810. DOI: 10.1016/j.cell.2008.04.049. View

Montpetit B, Conibear E . Identification of the novel TRAPP associated protein Tca17. Traffic. 2009; 10(6):713-23. DOI: 10.1111/j.1600-0854.2009.00895.x. View

Galindo A, Planelles-Herrero V, Degliesposti G, Munro S . Cryo-EM structure of metazoan TRAPPIII, the multi-subunit complex that activates the GTPase Rab1. EMBO J. 2021; 40(12):e107608. PMC: 8204870. DOI: 10.15252/embj.2020107608. View

Zong M, Wu X, Chan C, Choi M, Chan H, Tanner J . The adaptor function of TRAPPC2 in mammalian TRAPPs explains TRAPPC2-associated SEDT and TRAPPC9-associated congenital intellectual disability. PLoS One. 2011; 6(8):e23350. PMC: 3156116. DOI: 10.1371/journal.pone.0023350. View

Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T . ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016; 44(W1):W344-50. PMC: 4987940. DOI: 10.1093/nar/gkw408. View

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

10.

Sakaguchi A, Sato M, Sato K, Gengyo-Ando K, Yorimitsu T, Nakai J . REI-1 Is a Guanine Nucleotide Exchange Factor Regulating RAB-11 Localization and Function in C. elegans Embryos. Dev Cell. 2015; 35(2):211-21. DOI: 10.1016/j.devcel.2015.09.013. View

11.

Thomas L, van der Vegt S, Fromme J . A Steric Gating Mechanism Dictates the Substrate Specificity of a Rab-GEF. Dev Cell. 2018; 48(1):100-114.e9. PMC: 6324938. DOI: 10.1016/j.devcel.2018.11.013. View

12.

Choi C, Davey M, Schluter C, Pandher P, Fang Y, Foster L . Organization and assembly of the TRAPPII complex. Traffic. 2011; 12(6):715-25. DOI: 10.1111/j.1600-0854.2011.01181.x. View

13.

Benli M, Doring F, Robinson D, Yang X, Gallwitz D . Two GTPase isoforms, Ypt31p and Ypt32p, are essential for Golgi function in yeast. EMBO J. 1996; 15(23):6460-75. PMC: 452471. View

14.

Punjani A, Rubinstein J, Fleet D, Brubaker M . cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods. 2017; 14(3):290-296. DOI: 10.1038/nmeth.4169. View

15.

Mohamoud H, Ahmed S, Jelani M, Alrayes N, Childs K, Vadgama N . A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features. Sci Rep. 2018; 8(1):2053. PMC: 5794855. DOI: 10.1038/s41598-018-20658-w. View

16.

Segev N . Mediation of the attachment or fusion step in vesicular transport by the GTP-binding Ypt1 protein. Science. 1991; 252(5012):1553-6. DOI: 10.1126/science.1904626. View

17.

Humphreys I, Pei J, Baek M, Krishnakumar A, Anishchenko I, Ovchinnikov S . Computed structures of core eukaryotic protein complexes. Science. 2021; 374(6573):eabm4805. PMC: 7612107. DOI: 10.1126/science.abm4805. View

18.

Jenkins M, Harris N, Dalwadi U, Fleming K, Ziemianowicz D, Rafiei A . The substrate specificity of the human TRAPPII complex's Rab-guanine nucleotide exchange factor activity. Commun Biol. 2020; 3(1):735. PMC: 7719173. DOI: 10.1038/s42003-020-01459-2. View

19.

Taussig D, Lipatova Z, Kim J, Zhang X, Segev N . Trs20 is required for TRAPP II assembly. Traffic. 2013; 14(6):678-90. PMC: 3660434. DOI: 10.1111/tra.12065. View

20.

Borchers A, Langemeyer L, Ungermann C . Who's in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond. J Cell Biol. 2021; 220(9). PMC: 8366711. DOI: 10.1083/jcb.202105120. View