ArticleProceedings of the National Academy of Sciences of the United States of America2014
The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed.
- Heterogenous Neuropathology in a Pedigree with RAB39B-Related Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Structural insights into traffic through the Golgi complex.Current opinion in cell biology · 2025Review
- A tale of Rabs and the exocyst complex in ciliary trafficking and biogenesis.Frontiers in cell and developmental biology · 2025Review
- Structural basis for Rab6 activation by the Ric1-Rgp1 complex.Nature communications · 2024Article
- From disorder comes function: Regulation of small GTPase function by intrinsically disordered lipidated membrane anchor.Current opinion in structural biology · 2024Review
- Prediction of Rab5B inhibitors through integrative in silico techniques.Molecular diversity · 2024Article
- Article
- Structural basis for Rab6 activation by the Ric1-Rgp1 complex.bioRxiv : the preprint server for biology · 2024Article
- Structure of a membrane tethering complex incorporating multiple SNAREs.Nature structural & molecular biology · 2024Article
- Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence.Life science alliance · 2023Article
- The TRAPP complexes: oligomeric exchange factors that activate the small GTPases Rab1 and Rab11.FEBS letters · 2023Review
- Conserved but not critical: Trafficking and function of NaFrontiers in molecular neuroscience · 2023Article
- Article
- Clinical characterization of a novel RAB39B nonstop mutation in a family with ASD and severe ID causing RAB39B downregulation and study of a Rab39b knock down mouse model.Human molecular genetics · 2022Article
- A peptide derived from the N-terminus of charged multivesicular body protein 6 (CHMP6) promotes the secretion of gene editing proteins via small extracellular vesicle production.Bioengineered · 2022Article
- A cell-based GEF assay reveals new substrates for DENN domains and a role for DENND2B in primary ciliogenesis.Science advances · 2022Article
- RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein.Autophagy · 2021Article
- Self-assemblies of Rab- and Arf-family small GTPases on lipid bilayers in membrane tethering.Biophysical reviews · 2021Review
- Parkinson's Disease-Related Genes and Lipid Alteration.International journal of molecular sciences · 2021Review
- Cryo-EM structure of metazoan TRAPPIII, the multi-subunit complex that activates the GTPase Rab1.The EMBO journal · 2021Article
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6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intracellular membrane trafficking requires correct and specific localization of Rab GTPases. The hypervariable C-terminal domain (HVD) of Rabs is posttranslationally modified by isoprenyl moieties that enable membrane association. A model asserting HVD-directed targeting has been contested in previous studies, but the role of the Rab HVD and the mechanism of Rab membrane targeting remain elusive. To elucidate the function of the HVD, we have substituted this region with an unnatural polyethylenglycol (PEG) linker by using oxime ligation. The PEGylated Rab proteins undergo normal prenylation, underlining the unique ability of the Rab prenylation machinery to process the Rab family with diverse C-terminal sequences. Through localization studies and functional analyses of semisynthetic PEGylated Rab1, Rab5, Rab7, and Rab35 proteins, we demonstrate that the role of the HVD of Rabs in membrane targeting is more complex than previously understood. The HVD of Rab1 and Rab5 is dispensable for membrane targeting and appears to function simply as a linker between the GTPase domain and the membrane. The N-terminal residues of the Rab7 HVD are important for late endosomal/lysosomal localization, apparently due to their involvement in interaction with the Rab7 effector Rab-interacting lysosomal protein. The C-terminal polybasic cluster of the Rab35 HVD is essential for plasma membrane (PM) targeting, presumably because of the electrostatic interaction with negatively charged lipids on the PM. Our findings suggest that Rab membrane targeting is dictated by a complex mechanism involving GEFs, GAPs, effectors, and C-terminal interaction with membranes to varying extents, and possibly other binding partners.
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