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The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting

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The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting. / Li, Fu; Yi, Long; Zhao, Lei; Itzen, Aymelt; Goody, Roger S; Wu, Yao-Wen.

in: P NATL ACAD SCI USA, Jahrgang 111, Nr. 7, 18.02.2014, S. 2572-7.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Li, F, Yi, L, Zhao, L, Itzen, A, Goody, RS & Wu, Y-W 2014, 'The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting', P NATL ACAD SCI USA, Jg. 111, Nr. 7, S. 2572-7. https://doi.org/10.1073/pnas.1313655111

APA

Li, F., Yi, L., Zhao, L., Itzen, A., Goody, R. S., & Wu, Y-W. (2014). The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting. P NATL ACAD SCI USA, 111(7), 2572-7. https://doi.org/10.1073/pnas.1313655111

Vancouver

Li F, Yi L, Zhao L, Itzen A, Goody RS, Wu Y-W. The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting. P NATL ACAD SCI USA. 2014 Feb 18;111(7):2572-7. https://doi.org/10.1073/pnas.1313655111

Bibtex

@article{9e98a7ea71a44c23abe206992a91caea,
title = "The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting",
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. ",
keywords = "Animals, Cell Membrane, Dogs, Genetic Variation, HeLa Cells, Humans, Madin Darby Canine Kidney Cells, Models, Biological, Protein Structure, Tertiary, Protein Transport, rab GTP-Binding Proteins, Journal Article, Research Support, Non-U.S. Gov't",
author = "Fu Li and Long Yi and Lei Zhao and Aymelt Itzen and Goody, {Roger S} and Yao-Wen Wu",
year = "2014",
month = feb,
day = "18",
doi = "10.1073/pnas.1313655111",
language = "English",
volume = "111",
pages = "2572--7",
journal = "P NATL ACAD SCI USA",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "7",

}

RIS

TY - JOUR

T1 - The role of the hypervariable C-terminal domain in Rab GTPases membrane targeting

AU - Li, Fu

AU - Yi, Long

AU - Zhao, Lei

AU - Itzen, Aymelt

AU - Goody, Roger S

AU - Wu, Yao-Wen

PY - 2014/2/18

Y1 - 2014/2/18

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Membrane

KW - Dogs

KW - Genetic Variation

KW - HeLa Cells

KW - Humans

KW - Madin Darby Canine Kidney Cells

KW - Models, Biological

KW - Protein Structure, Tertiary

KW - Protein Transport

KW - rab GTP-Binding Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1073/pnas.1313655111

DO - 10.1073/pnas.1313655111

M3 - SCORING: Journal article

C2 - 24550285

VL - 111

SP - 2572

EP - 2577

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 7

ER -