Structural determinants of Rab11 activation by the guanine nucleotide exchange factor SH3BP5

Jenkins, Meredith L.; Margaria, Jean Piero; Stariha, Jordan T B; Hoffmann, Reece M.; McPhail, Jacob A.; Hamelin, David; Boulanger, Martin J.; Hirsch, Emilio; Burke, John E.

doi:10.1038/s41467-018-06196-z

Cited by 35 publications

(41 citation statements)

References 70 publications

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“…In Drosophila, these complexes were shown to activate Rab11 (Ypt31 homolog) and Rab1 (Ypt1 homolog), respectively , which is in agreement with the GEF specificity of the yeast complexes. Interestingly, the fact that TRAPP II‐specific subunits are essential in yeast and not in human cells (Table ) can be explained by the existence of an additional metazoan‐specific GEF for Rab11, SH3BP5 .…”

Section: Trapp Gefs At the Golgimentioning

confidence: 99%

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

Lipatova

Segev

2019

FEBS Letters

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The conserved Ypt/Rab GTPases regulate the different steps of all intracellular trafficking pathways. Ypt/Rabs are activated by their specific nucleotide exchangers termed GEFs, and when GTP bound, they recruit their downstream effectors, which mediate vesicular transport substeps. In the yeast exocytic pathway, Ypt1 and Ypt31/32 regulate traffic through the Golgi and the conserved modular TRAPP complex acts a GEF for both Ypt1 and Ypt31/32. However, the precise localization and function of these Ypts have been under debate, as is the identity of their corresponding GEFs. We have established that Ypt1 and Ypt31 reside on the two sides of the Golgi, early and late, respectively, and regulate Golgi cisternal progression. We and others have shown that whereas a single TRAPP complex, TRAPP II, activates Ypt31, three TRAPP complexes can activate Ypt1: TRAPPs I, III, and IV. We propose that TRAPP I and II activate Ypt1 and Ypt31, respectively, at the Golgi, whereas TRAPP III and IV activate Ypt1 in autophagy. Resolving these issues is important because both Rabs and TRAPPs are implicated in multiple human diseases, ranging from cancer to neurodegenerative diseases.

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Section: Trapp Gefs At the Golgimentioning

confidence: 99%

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

Lipatova

Segev

2019

FEBS Letters

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“…Additional GEFs, unrelated in structure to those in the last eukaryotic common ancestor have arisen for some Rabs. In metazoans, Rab11 has two GEFs, the ancestral TRAPPII complex and the SH3BP5/REI-1 GEF first discovered in C. elegans [19,20]. Exactly why metazoans have two distinct Rab11 GEFs remains unclear, since work in D. melanogaster shows that while Rab11 is an essential gene, SH3BP5 and the specific subunits of TRAPPII are not essential and instead they act redundantly [21].…”

Section: Co-evolution Of Rab Gefs and Vesicle Coat Complexesmentioning

confidence: 99%

Rab regulation by GEFs and GAPs during membrane traffic

Lamber

Siedenburg

Barr

2019

Current Opinion in Cell Biology

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Rab GTPases and their regulatory proteins play a crucial role in vesiclemediated membrane trafficking. During vesicle membrane tethering Rab GTPases are activated by GEFs (guanine nucleotide exchange factors) and then inactivated by GAPs (GTPase activating proteins). Recent evidence shows that in addition to activating and inactivating Rab GTPases, both Rab GEFs and GAPs directly contribute to membrane tethering events during vesicle traffic. Other studies have extended the range of processes in which Rabs function, and revealed roles for Rabs and their GAPs in the regulation of autophagy. Here we will discuss these advances and the emerging relationship between the domain architectures of Rab GEFs and vesicle coat protein complexes linked with GTPases of the Sar, ARF and Arl families in animal cells. Rab GTPases underpin eukaryotic membrane traffic Soon after their discovery three decades ago, it was appreciated that Rab GTPases localise to specific membrane domains and organelle membranes within eukaryotic cells [1]. This led to the idea that Rab GTPases proofread the interaction between a vesicle and its target membrane prior to the membrane fusion reaction and thus act as key regulators of membrane traffic [2]. Subsequently, this idea has been further developed based on observations that Rabs recruit the components of physical tethers to membrane surfaces during vesicle docking [1]. To fulfil this function, Rabs interact with specific effector proteins and must be activated and inactivated in a manner that is coordinated with the processes of vesicle formation, by coat protein complexes, and vesicle fusion, mediated by the SNARE proteins (Figure 1A and 1B).

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“…Two of these are of the same complex structure (SH3BP5:Rab11). Structural studies of SH3BP5 shows that its characteristic coiled-coil architecture mediates nucleotide exchange through its unique Rab-GEF interaction [62,63].…”

Section: Gef Structures and Mechanisms Of Small Gtpase Activationmentioning

confidence: 99%

Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

Toma-Fukai

Shimizu

2019

Molecules

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Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). The intrinsic GTP hydrolysis activity of small GTPases is generally low and is accelerated by GAPs. GEFs promote GDP dissociation from small GTPases to allow for GTP binding, which results in a conformational change of two highly flexible segments, called switch I and switch II, that enables binding of the gamma phosphate and allows small GTPases to interact with downstream effectors. For several decades, crystal structures of many GEFs and GAPs have been reported and have shown tremendous structural diversity. In this review, we focus on the latest structural studies of GEFs. Detailed pictures of the variety of GEF mechanisms at atomic resolution can provide insights into new approaches for drug discovery.

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Structural determinants of Rab11 activation by the guanine nucleotide exchange factor SH3BP5

Cited by 35 publications

References 70 publications

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

Ypt/Rab GTPases and their TRAPP GEFs at the Golgi

Rab regulation by GEFs and GAPs during membrane traffic

Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

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