Year: 2021
Type: article
Abstract: The GTPase Rab1 is a master regulator of the early secretory pathway and is critical for autophagy. Rab1 activation is controlled by its guanine nucleotide exchange factor, the multisubunit TRAPPIII complex. Here, we report the 3.7 Å cryo-EM structure of the Saccharomyces cerevisiae TRAPPIII complex bound to its substrate Rab1/Ypt1. The structure reveals the binding site for the Rab1/Ypt1 hypervariable domain, leading to a model for how the complex interacts with membranes during the activation reaction. We determined that stable membrane binding by the TRAPPIII complex is required for robust activation of Rab1/Ypt1 in vitro and in vivo, and is mediated by a conserved amphipathic α-helix within the regulatory Trs85 subunit. Our results show that the Trs85 subunit serves as a membrane anchor, via its amphipathic helix, for the entire TRAPPIII complex. These findings provide a structural understanding of Rab activation on organelle and vesicle membranes.
Source: The EMBO Journal
Institutions: Cornell University, MRC Laboratory of Molecular Biology
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,200
Funders: National Science Foundation, Alfred P. Sloan Foundation, Wellcome Trust, Diamond Light Source, National Institutes of Health, Cornell Center for Materials Research, Materials Research Science and Engineering Center, Harvard University, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Institute of General Medical Sciences, Division of Materials Research, Division of Graduate Education, Division of Biological Infrastructure, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1205195086, G1321126357, Quantifying molecular consequences of human missense variants with large-scale interactome perturbation studies, G2072083609, G2127518181, G2318728625, G2415270547, G2929996310, Collaborative Research: ABI Innovation: A Graph Based Approach for the Genome Wide Prediction of Conditionally Essential Genes, Regulation of Arf GTPase activation at the Golgi complex, G4019945064, Cornell Center for Materials Research - MRSEC, Regulation of Rab activation at the Golgi complex, G4989108295, G5917061246, Towards a comprehensive multiscale 3D human interactome network, Cellular responses to DNA replication stress, G6351810044, Graduate Research Fellowship Program (GRFP), G7767248047, G8229174675, GTPase Regulation of the Golgi Complex, Signaling Mechanisms in Genome Maintenance, Coordination of Atr Signaling for Genetic Quality Control, Silencing, and DNA Repair during Meiosis
OpenAlex ID: W3160486644