RanGAP mediates GTP hydrolysis without an arginine finger

Seewald, Michael; Körner, Carolin; Wittinghofer, Alfred; Vetter, Ingrid R.

doi:10.1038/415662a

Cited by 196 publications

(189 citation statements)

References 30 publications

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“…In opisthokonts, Ran, RBP1 and Ran-GAP work in synchrony to expedite the hydrolysis of RanGTP to RanGDP in the cytoplasm to facilitate the release of protein cargo from a RanGTP-karyopherin complex. [53][54][55] Therefore, the co-isolation of Ran, RBP1 and the GAP with the non-karyopherin transporters Mex67-Mtr2 is extremely unusual and has not been previously observed in other organisms. This suggests that unlike in opisthokonts and plants, GTP and not ATP powers mRNA export in trypanosomes.…”

Section: Tms and Alps: Multiple Ways To Tether A Leviathanmentioning

confidence: 85%

Comparative interactomics provides evidence for functional specialization of the nuclear pore complex

Obado

Field

Rout

2017

Nucleus

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The core architecture of the eukaryotic cell was established well over one billion years ago, and is largely retained in all extant lineages. However, eukaryotic cells also possess lineagespecific features, frequently keyed to specific functional requirements. One quintessential core eukaryotic structure is the nuclear pore complex (NPC), responsible for regulating exchange of macromolecules between the nucleus and cytoplasm as well as acting as a nuclear organizational hub. NPC architecture has been best documented in one eukaryotic supergroup, the Opisthokonts (e.g. Saccharomyces cerevisiae and Homo sapiens), which although compositionally similar, have significant variations in certain NPC subcomplex structures. The variation of NPC structure across other taxa in the eukaryotic kingdom however, remains poorly understood. We explored trypanosomes, highly divergent organisms, and mapped and assigned their NPC proteins to specific substructures to reveal their NPC architecture. We showed that the NPC central structural scaffold is conserved, likely across all eukaryotes, but more peripheral elements can exhibit very significant lineage-specific losses, duplications or other alterations in their components. Amazingly, trypanosomes lack the major components of the mRNA export platform that are asymmetrically localized within yeast and vertebrate NPCs. Concomitant with this, the trypanosome NPC is ALMOST completely symmetric with the nuclear basket being the only major source of asymmetry. We suggest these features point toward a stepwise evolution of the NPC in which a coating scaffold first stabilized the pore after which selective gating emerged and expanded, leading to the addition of peripheral remodeling machineries on the nucleoplasmic and cytoplasmic sides of the pore.

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Section: Tms and Alps: Multiple Ways To Tether A Leviathanmentioning

confidence: 85%

Comparative interactomics provides evidence for functional specialization of the nuclear pore complex

Obado

Field

Rout

2017

Nucleus

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“…All these tails (RMSD, 4.9 Å) had the same central helix (aa 196-206), but none were similarly oriented relative to the core. Among Ran structures solved by crystallography, the COOH tail arrangements can vary according to nucleotide status and binding partner-induced shifts that may also involve the nucleotideproximal phosphate binding P-loop (aa [16][17][18][19][20][21][22][23][24][25], Switch 1 (aa 32-45), Switch 2 (aa 66-79), and basic patch (aa 139-142) internal core segments (Fig. 3) …”

Section: Significancementioning

confidence: 99%

“…1A). The change is in a conserved, amino-proximal CHCC zinc finger motif (aa [10][11][12][13][14][15][16][17][18][19][20][21][22], the structure of which was determined by NMR for the L M protein (14). Technical difficulties hampered resolution of the complete protein, but a full coordinate set was recently completed [Protein Data Bank (PDB) ID code 2M7Y].…”

mentioning

confidence: 99%

Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase

Bacot‐Davis

Ciomperlik

Basta

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cardiovirus Leader (L) proteins induce potent antihost inhibition of active cellular nucleocytoplasmic trafficking by triggering aberrant hyperphosphorylation of nuclear pore proteins (Nup). To achieve this, L binds protein RanGTPase (Ran), a key trafficking regulator, and diverts it into tertiary or quaternary complexes with required kinases. The activity of L is regulated by two phosphorylation events not required for Ran binding. Matched NMR studies on the unphosphorylated, singly, and doubly phosphorylated variants of Mengovirus L (L M ) show both modifications act together to partially stabilize a short internal α-helix comprising L M residues 43-46. This motif implies that ionic and Van der Waals forces contributed by phosphorylation help organize downstream residues 48-67 into a new interface. The full structure of L M as bound to Ran (unlabeled) and Ran (216 aa

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“…Glutamine and arginine residues in GAPs such as Ras⅐GAP, p50Rho⅐GAP, cdc42⅐GAP, and the yeast Ypt/Rab⅐GAP⅐Gyp1p are critical in mimicking residues in their respective G proteins to stabilize the transition phase of the G␣ i binding pocket (10 -12, 14, 23, 39). The contribution of the tyrosine residue is less clear, although some studies imply that a tyrosine hydroxyl on the G protein itself (11,12,15,40) or the GAP in the case of the RGS4⅐G␣ i interaction (24) is part of a network providing polar interaction between the G domain and GAP, facilitating catalysis. Our data support a role for the tyrosine hydroxyl in reducing rather than enhancing catalysis.…”

Section: Fig 5 Tyrosine Phosphorylation In Gap Motifs Of the Kir34mentioning

confidence: 99%

N-terminal Tyrosine Residues within the Potassium Channel Kir3 Modulate GTPase Activity of Gαi

Ippolito

Temkin

Rogalski

et al. 2002

Journal of Biological Chemistry

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trkB activation results in tyrosine phosphorylation of N-terminal Kir3 residues, decreasing channel activation. To determine the mechanism of this effect, we reconstituted Kir3, trkB, and the mu opioid receptor in Xenopus oocytes. Activation of trkB by BDNF (brainderived neurotrophic factor) accelerated Kir3 deactivation following termination of mu opioid receptor signaling. Similarly, overexpression of RGS4, a GTPaseactivating protein (GAP), accelerated Kir3 deactivation. Blocking GTPase activity with GTP␥S also prevented Kir3 deactivation, and the GTP␥S effect was not reversed by BDNF treatment. These results suggest that BDNF treatment did not reduce Kir3 affinity for G␤␥ but rather acted to accelerate GTPase activity, like RGS4. Tyrosine phosphatase inhibition by peroxyvanadate pretreatment reversibly mimicked the BDNF/trkB effect, indicating that tyrosine phosphorylation of Kir3 may have caused the GTPase acceleration. Tyrosine to phenylalanine substitution in the N-terminal domain of Kir3.4 blocked the BDNF effect, supporting the hypothesis that phosphorylation of these tyrosines was responsible. Like other GAPs, Kir3.4 contains a tyrosine-arginine-glutamine motif that is thought to function by interacting with G protein catalytic domains to facilitate GTP hydrolysis. These data suggest that the N-terminal tyrosine hydroxyls in Kir3 normally mask the GAP activity and that modification by phosphorylation or phenylalanine substitution reveals the GAP domain. Thus, BDNF activation of trkB could inhibit Kir3 by facilitating channel deactivation.The family of G protein-activated potassium channels (Kir3 or GIRK) 1 is a principal effector mediating the actions of a wide range of pertussis toxin-sensitive, G protein-coupled receptors (GPCR) (1). Channel activation provides key regulation of both cardiac and neuronal excitability. The activity of this channel is controlled by a large number of modulators including phosphatidylinositol bisphosphate, Na ϩ , eicosanoids, ATP, Mg 2ϩ , and phosphorylation (1-6). For example, in a previous study (7), we found that tyrosine phosphorylation of Kir3 resulted in channel inhibition. Brain-derived neurotrophic factor (BDNF) activation of trkB receptors caused the phosphorylation of specific tyrosine residues in the N-terminal domain of Kir3.1 and Kir3.4, reducing basal channel conductance. G␤␥, released by opioid receptor activation, overcame the inhibition and evoked the original maximal effect. The results suggest that channel phosphorylation regulates the specific interaction with G␤␥, but the mechanism of this effect is unclear. However, the finding may be physiologically significant because tyrosine kinase cascades initiated by neurotrophic factors such as BDNF and nerve growth factor are up-regulated under conditions such as inflammation (8). It is possible that tyrosine phosphorylation of Kir3 may mediate neuronal excitability in conjunction with GPCRs under conditions of inflammation. The goal of the present study was to define the mechanism responsible for BDNF inhib...

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RanGAP mediates GTP hydrolysis without an arginine finger

Cited by 196 publications

References 30 publications

Comparative interactomics provides evidence for functional specialization of the nuclear pore complex

Comparative interactomics provides evidence for functional specialization of the nuclear pore complex

Solution structures of Mengovirus Leader protein, its phosphorylated derivatives, and in complex with nuclear transport regulatory protein, RanGTPase

N-terminal Tyrosine Residues within the Potassium Channel Kir3 Modulate GTPase Activity of Gαi

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