Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Mar;597(6):721-733.
doi: 10.1002/1873-3468.14557. Epub 2022 Dec 21.

The TRAPP complexes: discriminating GTPases in context

Saket R Bagde  1 , J Christopher Fromme  1
Affiliations
Review

The TRAPP complexes: discriminating GTPases in context

Saket R Bagde et al. FEBS Lett. 2023 Mar.

Abstract

Correct localization of Rab GTPases in cells is critical for proper function in membrane trafficking. Guanine-nucleotide exchange factors (GEFs) act as the primary determinants of Rab localization by activating and stabilizing their Rab substrates on specific organelle and vesicle membranes. The TRAPP complexes TRAPPII and TRAPPIII are two related GEFs that use the same catalytic site to activate distinct Rabs, Rab11 and Rab1, respectively. The Rab C-terminal hypervariable domain (HVD) is an important specificity determinant for the budding yeast TRAPP complexes, with the length of the HVD playing a critical role in counter-selection. Several recent studies have used cryo-EM to illuminate how the yeast and metazoan TRAPP complexes identify and activate their substrates. This review summarizes recently characterized Rab substrate selection mechanisms and highlights how the membrane surface provides critical context for the GEF-GTPase interactions.

Keywords: GTPase; Rab; TRAPP; guanine-nucleotide exchange factor; membrane trafficking.

PubMed Disclaimer

Figures

Fig. 1:
Fig. 1:. Composition and structures of the budding yeast TRAPP complexes.
(A) Subunit compositions of the budding yeast TRAPPII and TRAPPIII complexes. (B) cryo-EM structure of the budding yeast TRAPPIII complex bound to Rab1/Ypt1 [54]. (C) cryo-EM structure of the budding yeast TRAPPII complex bound to Rab11/Ypt32 [60].
Fig. 2:
Fig. 2:. Specific activation of the Rab substrates by the TRAPP complexes.
(A) The catalytic core stabilizes the nucleotide free form of Rab1/Ypt1 to facilitate nucleotide exchange. The close-up view shows the GDP bound crystal structure of mammalian RAB1A (PDB: 2FOL) superposed onto the nucleotide free form of Rab1/Ypt1 bound to the catalytic core in the budding yeast TRAPPIII-Rab1/Ypt1 cryo-EM structure (PDB: 7KMT). (B) Repulsive interactions near the Rab11/Ypt32-catalytic core interface. The bottom panel shows the Rab11/Ypt32, Rab1/Ypt1, and catalytic core surfaces colored by electrostatic potential. Dashed ovals denote the surfaces in Rab11/Ypt32 and the catalytic core that participate in the repulsive interaction and the corresponding surface in Rab1/Ypt1. (C) Predicted orientation of TRAPPII on a membrane. Rab1/Ypt1 is superposed onto the catalytic core of TRAPPII to demonstrate that the Rab1/Ypt1 HVD cannot bridge the distance between the catalytic core in TRAPPII and the membrane. (D) Close-up view of Rab11 bound to TRAPPII highlighting the role of Trs120 in providing an additional interface with Rab11 NBD, acting as a lid for the TRAPPII active site chamber.
Fig. 3:
Fig. 3:. Model for activation of Rab1/Ypt1 and Rab11/Ypt32 on the membrane by the TRAPP complexes.
(A) TRAPPIII binds to membranes containing anionic lipids via an amphipathic helix in Trs85. GDP-bound Rab1/Ypt1 binds to the catalytic core, triggering conformational change of Rab1/Ypt1 and GDP release. Binding of GTP triggers another conformational change to yield active Rab1/Ypt1 and dissociation from the catalytic core. (B) TRAPPII is recruited to anionic membranes by GTP-bound Arf1. A TRAPPII monomer switches to the open conformation allowing GDP-bound Rab11/Ypt32 to access the active site chamber. Rab11/Ypt32 binds the catalytic core and nucleotide exchange occurs once the monomer switches to the closed conformation. GTP-bound Rab11 exits the active site chamber once the monomer again adopts the open conformation.
Fig. 4:
Fig. 4:. Metazoan TRAPP complexes.
(A) Metazoan TRAPP subunits and their budding yeast homologs. (B) Subunit composition of metazoan TRAPP complexes. (C) Composite cryo-EM map of the Drosophila TRAPPIII complex (EMD-12052, EMD-12053 and EMD-12054) [55]. Rab1 (translucent purple) is superposed onto the catalytic core based on the location of Rab1/Ypt1 bound to the yeast catalytic core. (D) Cryo-EM map of the budding yeast TRAPPIII complex bound to Rab1/Ypt1 [54] for comparison.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Pfeffer SR (2017) Rab GTPases: master regulators that establish the secretory and endocytic pathways. Mol Biol Cell 28, 712–715. - PMC - PubMed
    1. 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. - PMC - PubMed
    1. Borchers A-C, Langemeyer L & Ungermann C (2021) Who’s in control? Principles of Rab GTPase activation in endolysosomal membrane trafficking and beyond. J Cell Biol 220. - PMC - PubMed
    1. Barr F & Lambright DG (2010) Rab GEFs and GAPs. Curr Opin Cell Biol 22, 461–470. - PMC - PubMed
    1. Lamber EP, Siedenburg A-C & Barr FA (2019) Rab regulation by GEFs and GAPs during membrane traffic. Curr Opin Cell Biol 59, 34–39. - PubMed

Publication types

MeSH terms

Substances

Supplementary concepts