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Sec7 regulatory domains scaffold autoinhibited and active conformations
Open accessPublished version of a preprint
Abstract
The late stages of Golgi maturation involve a series of sequential trafficking events in which cargo-laden vesicles are produced and targeted to multiple distinct subcellular destinations. Each of these vesicle biogenesis events requires activation of an Arf GTPase by the Sec7/BIG guanine nucleotide exchange factor (GEF). Sec7 localization and activity is regulated by autoinhibition, positive feedback, and interaction with other GTPases. Although these mechanisms have been characterized biochemically, we lack a clear picture of how GEF localization and activity is modulated by these signals. Here, we report the cryogenic electron microscopy structure of full-length Sec7 in its autoinhibited form, revealing the architecture of its multiple regulatory domains. We use functional experiments to determine the basis for autoinhibition and use structural predictions to produce a model for an active conformation of the GEF that is supported empirically. This study therefore elucidates the conformational transition that Sec7 undergoes to become active on the organelle membrane surface.
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Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics
Iversen, L., Tu, H.-L., Lin, W.-C., Christensen, S. M., Abel, S. M., Iwig, J., Wu, H.-J., Gureasko, J., Rhodes, C., Petit, R. S., et al. (2014) · Science · doi:10.1126/science.1250373 · Cited by 154
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Metadata
- Authors
- Brownfield, B. A., Richardson, B. C., Halaby, S. L., & Fromme, J. C.
- Affiliations
- Cornell University (US)
- Corresponding author
- Fromme, J. Christopher
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2024-02-28
- Volume
- 121
- Issue
- 10
- Pages
- e2318615121-e2318615121
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC10927569
- OpenAlex
- W4392242827
- Cited by
- 5
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- HHS | NIH | National Institute of General Medical Sciences (R35GM136258)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- autoinhibition, conformational change, Golgi maturation, regulatory domain, vesicle trafficking, GTPase activation, cryo-EM structure
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