Allosteric properties of PH domains in Arf regulatory proteins

Roy, Nirmolendu; Yohe, Marielle E.; Randazzo, Paul A.; Gruschus, James M.

doi:10.1080/21592799.2016.1181700

Cited by 12 publications

(10 citation statements)

References 113 publications

(149 reference statements)

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“…Conversely, increased PI(4,5)P 2 production caused Rab7 inactivation, which indicates either activation of a Rab7 GAP protein, or inactivation of the Rab7 GEF protein. It has been well documented that many GAP proteins mostly acting on Arf proteins are activated by PI(4,5)P 2 (Roy et al , ). On the other hand, to our knowledge no study has reported inositol lipids inhibiting a GEF protein.…”

Section: Resultsmentioning

confidence: 99%

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

et al. 2019

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The small GTPase Rab7 is a key organizer of receptor sorting and lysosomal degradation by recruiting of a variety of effectors depending on its GDP/GTP‐bound state. However, molecular mechanisms that trigger Rab7 inactivation remain elusive. Here we find that, among the endosomal pools, Rab7‐positive compartments possess the highest level of PI4P, which is primarily produced by PI4K2A kinase. Acute conversion of this endosomal PI4P to PI(4,5)P2 causes Rab7 dissociation from late endosomes and releases a regulator of autophagosome–lysosome fusion, PLEKHM1, from the membrane. Rab7 effectors Vps35 and RILP are not affected by acute PI(4,5)P2 production. Deletion of PI4K2A greatly reduces PIP5Kγ‐mediated PI(4,5)P2 production in Rab7‐positive endosomes leading to impaired Rab7 inactivation and increased number of LC3‐positive structures with defective autophagosome–lysosome fusion. These results reveal a late endosomal PI4P‐PI(4,5)P2‐dependent regulatory loop that impacts autophagosome flux by affecting Rab7 cycling and PLEKHM1 association.

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Section: Resultsmentioning

confidence: 99%

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

et al. 2019

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“…BRAG1/IQSec2 binds to Ca 2+ -free calmodulin in vitro, and addition of Ca 2+ causes its dissociation from membranes (Aizel et al. , 2013; Roy et al. , 2016).…”

Section: Arf Gefsmentioning

confidence: 99%

ARF GTPases and their GEFs and GAPs: concepts and challenges

Sztul

Chen

Casanova

et al. 2019

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Detailed structural, biochemical, cell biological, and genetic studies of any gene/protein are required to develop models of its actions in cells. Studying a protein family in the aggregate yields additional information, as one can include analyses of their coevolution, acquisition or loss of functionalities, structural pliability, and the emergence of shared or variations in molecular mechanisms. An even richer understanding of cell biology can be achieved through evaluating functionally linked protein families. In this review, we summarize current knowledge of three protein families: the ARF GTPases, the guanine nucleotide exchange factors (ARF GEFs) that activate them, and the GTPase-activating proteins (ARF GAPs) that have the ability to both propagate and terminate signaling. However, despite decades of scrutiny, our understanding of how these essential proteins function in cells remains fragmentary. We believe that the inherent complexity of ARF signaling and its regulation by GEFs and GAPs will require the concerted effort of many laboratories working together, ideally within a consortium to optimally pool information and resources. The collaborative study of these three functionally connected families (≥70 mammalian genes) will yield transformative insights into regulation of cell signaling.

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“…Pathogenic variants are located within the IQ‐like domain (Shoubridge et al., ; Zerem et al., ; Zhang et al., ), Sec7 domain (de Kovel et al., ; Gandomi et al., ; Helbig, et al ., ; Helm et al., ; Kalscheuer et al., ; Mignot et al., ; Shoubridge et al., ), or PH domain (Helm et al., ; Mignot et al., ). The IQ‐like and Sec7 functional domains are both involved in catalytic activity of guanine nucleotide exchange and activation of the substrate ARF6, while the PH domain may be involved in IQSEC2‐accessory protein interactions, increasing the association of substrates (ARFGDP) with the catalytic Sec7 domain or recruiting IQSEC2 and associated signaling pathways to different subcellular compartments via interactions with phosphoinositides (Roy, Yohe, Randazzo, & Gruschus, ). Hence, the consequences of missense changes in these domains may cause a partial loss of IQSEC2 function either by impaired ARFGEF activity or mislocalization of IQSEC2 (Kalscheuer et al., ; Shoubridge et al., ).…”

Section: Genotype–phenotype Relationships Of Pathogenic Variants In Imentioning

confidence: 99%

IQSEC2mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy

2018

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The IQSEC2-related disorders represent a spectrum of X-chromosome phenotypes with intellectual disability (ID) as the cardinal feature. Here, we review the increasing number of reported families and isolated cases have been reported with a variety of different pathogenic variants. The spectrum of clinical features is expanding with early-onset seizures as a frequent comorbidity in both affected male and female patients. There is a growing number of female patients with de novo loss-of-function variants in IQSEC2 have a more severe phenotype than the heterozygous state would predict, particularly if IQSEC2 is thought to escape X-inactivation. Interestingly, these findings highlight that the classical understanding of X-linked inheritance does not readily explain the emergence of these affected females, warranting further investigations into the underlying mechanisms. K E Y W O R D Saffected females, escape X-inactivation, intellectual disability, IQSEC2, seizures

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Allosteric properties of PH domains in Arf regulatory proteins

Cited by 12 publications

References 113 publications

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

Phosphatidylinositol 4,5‐bisphosphate controls Rab7 and PLEKHM 1 membrane cycling during autophagosome–lysosome fusion

ARF GTPases and their GEFs and GAPs: concepts and challenges

IQSEC2mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy

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