Human atlastin GTPases mediate differentiated fusion of endoplasmic reticulum membranes

Hu, Xiaoyu; Wu, Fuyun; Sun, Sha; Yu, Wenying; Hu, Junjie

doi:10.1007/s13238-015-0139-3

Cited by 33 publications

(48 citation statements)

References 15 publications

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“…Previously, catalytic activities were shown to be qualitatively different for human ATL isoforms (Hu et al, 2015), an observation we confirm and expand on here. First, we determined apparent turnover numbers ( k cat ) for the catalytic core fragments of human ATL1 and ATL3, the most dissimilar isoforms in higher eukaryotes, by quantifying catalytic rates of phosphate release over a range of protein concentrations (Figure 1D).…”

Section: Resultssupporting

confidence: 88%

“…Functional redundancy has been shown for hATL1 and hATL2 due to their ability to restore a branched ER morphology when expressed in COS-7 cells devoid of all ATLs. However, hATL3 fails to fully rescue the branched ER phenotype suggesting that not all isoforms are mechanistically equivalent (Hu et al, 2015; Yan et al, 2015). Isoform differences have been shown biochemically through phosphate release kinetics, where hATL1 and hATL3 have the highest and lowest catalytic rates (Hu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…However, hATL3 fails to fully rescue the branched ER phenotype suggesting that not all isoforms are mechanistically equivalent (Hu et al, 2015; Yan et al, 2015). Isoform differences have been shown biochemically through phosphate release kinetics, where hATL1 and hATL3 have the highest and lowest catalytic rates (Hu et al, 2015). hATL1 and hATL3 are implicated in neurological disorders that are characterized by axonal degeneration, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin

et al. 2017

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Summary The endoplasmic reticulum (ER) forms a branched, dynamic membrane tubule network that is vital for cellular function. Branching arises from membrane fusion facilitated by the GTPase atlastin (ATL). Many metazoan genomes encode for three ATL isoforms that appear to fulfill partially redundant function despite differences in their intrinsic GTPase activity and localization within the ER; however, the underlying mechanistic differences between the isoforms are poorly understood. Here, we identify discrete temporal steps in the catalytic cycle for the two most dissimilar isoforms, ATL1 and ATL3, revealing an overall conserved progression of molecular events from nucleotide binding and hydrolysis, to ATL dimerization and phosphate release. A crystal structure of ATL3 suggests a mechanism for the displacement of the catalytic Mg2+ ion following GTP hydrolysis. Together, the data extend the mechanistic framework for how GTP hydrolysis drives conformational changes in ATL and how the cycle is reset for subsequent rounds of catalysis.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin

et al. 2017

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“…Genomes of higher eukaryotes typically encode three main ATL isoforms (ATL1-3), with ATL1 being enriched in neural tissues and ATL2 and ATL3 showing more ubiquitous expression patterns (16). On a molecular level, ATL isoforms vary in GTPase activity and their apparent distribution across the ER (27,28). ATL1 is the most active isoform in vitro and decorates the tubular ER network evenly in cells, whereas ATL3 is a less efficient enzyme and localizes preferentially to junction points in the ER network that appear to be associated with membrane fusion events (27)(28)(29).…”

mentioning

confidence: 99%

“…On a molecular level, ATL isoforms vary in GTPase activity and their apparent distribution across the ER (27,28). ATL1 is the most active isoform in vitro and decorates the tubular ER network evenly in cells, whereas ATL3 is a less efficient enzyme and localizes preferentially to junction points in the ER network that appear to be associated with membrane fusion events (27)(28)(29). A closer structural comparison of two ATL isoforms (ATL1 and ATL3) indicates that despite differences in GTP-hydrolysis kinetics, the overall sequence of molecular events leading to ATL dimerization (and presumably membrane fusion) is conserved (26).…”

mentioning

confidence: 99%

A hereditary spastic paraplegia–associated atlastin variant exhibits defective allosteric coupling in the catalytic core

O’Donnell

Byrnes²,

Cooley³

et al. 2018

Journal of Biological Chemistry

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The dynamin-related GTPase atlastin (ATL) catalyzes membrane fusion of the endoplasmic reticulum and thus establishes a network of branched membrane tubules. When ATL function is compromised, the morphology of the endoplasmic reticulum deteriorates, and these defects can result in neurological disorders such as hereditary spastic paraplegia and hereditary sensory neuropathy. ATLs harness the energy of GTP hydrolysis to initiate a series of conformational changes that enable homodimerization and subsequent membrane fusion. Disease-associated amino acid substitutions cluster in regions adjacent to ATL's catalytic site, but the consequences for the GTPase's molecular mechanism are often poorly understood. Here, we elucidate structural and functional defects of an atypical hereditary spastic paraplegia mutant, ATL1-F151S, that is impaired in its nucleotide-hydrolysis cycle but can still adopt a high-affinity homodimer when bound to a transition-state analog. Crystal structures of mutant proteins yielded models of the monomeric pre- and post-hydrolysis states of ATL. Together, these findings define a mechanism for allosteric coupling in which Phe is the central residue in a hydrophobic interaction network connecting the active site to an interdomain interface responsible for nucleotide loading.

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Identification of endoplasmic reticulum-shaping proteins in Plasmodium parasites

Sun

Yao

et al. 2016

Protein Cell

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Human atlastin GTPases mediate differentiated fusion of endoplasmic reticulum membranes

Cited by 33 publications

References 15 publications

Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin

Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin

A hereditary spastic paraplegia–associated atlastin variant exhibits defective allosteric coupling in the catalytic core

Identification of endoplasmic reticulum-shaping proteins in Plasmodium parasites

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