Remodeling of the interdomain allosteric linker upon membrane binding of CCTα pulls its active site close to the membrane surface

Knowles, Daniel G.; Lee, Jaeyong; Taneva, Svetla G.; Cornell, Rosemary B.

doi:10.1074/jbc.ra119.009850

Cited by 7 publications

(7 citation statements)

References 43 publications

(77 reference statements)

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“…1). The disposition of the ␣E C /J in relation to the catalytic domain and the membrane surface is explored in the companion paper (33). The emerging model presented here (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…The response includes hinge-induced reorientations, changes in solvent exposure, and new interactions forged by highly conserved residues. Data in the subsequent paper (33) suggest that the ␣E C and J segments are close to the membrane surface in CCT mem but are not membrane-penetrant and that they form a compact structure that brings the active site close to the membrane surface.…”

Section: The ␣E Helix Residues Tyr-213 and Tyr-216 Sample A Solvent-pmentioning

confidence: 95%

“…But surprisingly CCT-236 is weakly activated by lipids (Figs. 3-5), an effect that will be clarified in the companion paper (33). Thus, it is an imperfect model to use compared with CCT-312 to tease out the specific lipid-related effects from nonlipid-related effects on activity.…”

Section: ␣Ec/j Mutations Can Modulate Cct Activity Independent Of Dommentioning

confidence: 99%

“…In vitro and in vivo, a bent helix may be stabilized by interactions other than or in addition to the aromatic cluster. Possibilities, explored in the companion paper (33), include interactions with the J segment following the ␣E and/or the membrane surface.…”

Section: The ␣E Helix Residues Tyr-213 and Tyr-216 Sample A Solvent-pmentioning

confidence: 99%

See 3 more Smart Citations

Interdomain communication in the phosphatidylcholine regulatory enzyme, CCTα, relies on a modular αE helix

Taneva

Lee

Knowles

et al. 2019

Journal of Biological Chemistry

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“…1). The disposition of the ␣E C /J in relation to the catalytic domain and the membrane surface is explored in the companion paper (33). The emerging model presented here (Fig.…”

Section: Discussionmentioning

confidence: 98%

Section: The ␣E Helix Residues Tyr-213 and Tyr-216 Sample A Solvent-pmentioning

confidence: 95%

Section: ␣Ec/j Mutations Can Modulate Cct Activity Independent Of Dommentioning

confidence: 99%

Section: The ␣E Helix Residues Tyr-213 and Tyr-216 Sample A Solvent-pmentioning

confidence: 99%

See 2 more Smart Citations

Interdomain communication in the phosphatidylcholine regulatory enzyme, CCTα, relies on a modular αE helix

Taneva

Lee

Knowles

et al. 2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…Intriguingly, in Pf CCT, the single continuous m-AH in mammalian CCTs 23 is substituted by two separate amphipathic helices in the putative membrane binding domain, a shorter N-terminal and a longer C-terminal helices (m-AH-N and m-AH-C, respectively) 24 . Upon membrane tethering, the catalytic domain is released from autoinhibition, resulting in a dramatic increase of enzyme activity in mammalian CCTs 15 , 25 . Accordingly, an engineered CCT construct comprising the catalytic but not the membrane-binding domain possesses constitutive, lipid-independent enzyme activity 26 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a nuclear localization signal in the Plasmodium falciparum CTP: phosphocholine cytidylyltransferase enzyme

Izrael

Marton

Nagy

et al. 2020

Sci Rep

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The phospholipid biosynthesis of the malaria parasite, Plasmodium falciparum is a key process for its survival and its inhibition is a validated antimalarial therapeutic approach. The second and rate-limiting step of the de novo phosphatidylcholine biosynthesis is catalysed by CTP: phosphocholine cytidylyltransferase (PfCCT), which has a key regulatory function within the pathway. Here, we investigate the functional impact of the key structural differences and their respective role in the structurally unique pseudo-heterodimer PfCCT protein in a heterologous cellular context using the thermosensitive CCT-mutant CHO-MT58 cell line. We found that a Plasmodium-specific lysine-rich insertion within the catalytic domain of PfCCT acts as a nuclear localization signal and its deletion decreases the nuclear propensity of the protein in the model cell line. We further showed that the putative membrane-binding domain also affected the nuclear localization of the protein. Moreover, activation of phosphatidylcholine biosynthesis by phospholipase C treatment induces the partial nuclear-to-cytoplasmic translocation of PfCCT. We additionally investigated the cellular function of several PfCCT truncated constructs in a CHO-MT58 based rescue assay. In absence of the endogenous CCT activity we observed that truncated constructs lacking the lysine-rich insertion, or the membrane-binding domain provided similar cell survival ratio as the full length PfCCT protein.

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Tumor protein D54 binds intracellular nanovesicles via an extended amphipathic region

Reynaud

Magdeleine

Patel

et al. 2022

Journal of Biological Chemistry

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Remodeling of the interdomain allosteric linker upon membrane binding of CCTα pulls its active site close to the membrane surface

Cited by 7 publications

References 43 publications

Interdomain communication in the phosphatidylcholine regulatory enzyme, CCTα, relies on a modular αE helix

Interdomain communication in the phosphatidylcholine regulatory enzyme, CCTα, relies on a modular αE helix

Identification of a nuclear localization signal in the Plasmodium falciparum CTP: phosphocholine cytidylyltransferase enzyme

Tumor protein D54 binds intracellular nanovesicles via an extended amphipathic region

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