PEP-19 modulates calcium binding to calmodulin by electrostatic steering

Wang, Xu; Putkey, John A.

doi:10.1038/ncomms13583

Cited by 22 publications

(15 citation statements)

References 43 publications

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“…Triton X-100 binds to most proteins via both hydrophobic and polar interactions (Singh and Kishore, 2006) and may thereby disrupt protein-protein interactions at high concentrations. An example of a calmodulin-interacting protein that is important for the calmodulin-IQ interaction is PEP-19 which binds to the C-terminal domain of calmodulin and electrostatically steers it to interact with the IQ domain (Wang and Putkey, 2016). We interpreted these results as indicating that normally calcium stimulates calmodulin binding to IQSEC2 and that the results of Myers showing calcium reduces the binding of calmodulin to IQSEC2 were artifacts related to the high Triton concentration used.…”

Section: Resultsmentioning

confidence: 99%

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Rogers

Jada

Schragenheim-Rozales

et al. 2019

Front. Mol. Neurosci.

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We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy.

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Section: Resultsmentioning

confidence: 99%

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Rogers

Jada

Schragenheim-Rozales

et al. 2019

Front. Mol. Neurosci.

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“…The results of prior studies indicate a function for PCP4/PEP-19 in Ca 2þ homeostasis by modifying agonist-induced Ca 2þ release. 11,17,47 Here, we explored the potential role of PCP4/PEP-19 in maintaining quiescence by regulating agonist-induced Ca 2þ mobilization. Myometrial cells respond to uterotonic stimuli such as oxytocin by activating signaling cascades, leading to changes in intracellular Ca 2þ levels, which in turn, through the regulation of Ca 2þ -CaM, affects various cellular processes including the activity of the actin-myosin contractile apparatus.…”

Section: Discussionmentioning

confidence: 99%

Expression, Regulation, and Function of the Calmodulin Accessory Protein PCP4/PEP-19 in Myometrium

Lee

Zhou

et al. 2019

Reprod. Sci.

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Objective: Calmodulin (CaM) plays a key role in the orchestration of Ca2+ signaling events, and its regulation is considered an important component of cellular homeostasis. The control of uterine smooth muscle function is largely dependent on the regulation of Ca2+ and CaM signaling. The objective of this study was to investigate the expression, function, and regulation of CaM regulatory proteins in myometrium during pregnancy. Study Design: Myometrium was obtained from nonpregnant women and 4 groups of pregnant women at the time their primary cesarean delivery: (i) preterm not in labor, (ii) preterm in labor with clinical and/or histological diagnosis of chorioamnionitis, (3) term not in labor; and (4) term in labor. The effect of perinatal inflammation on pcp4/pep-19 expression was evaluated in a mouse model of Ureaplasma parvum-induced chorioamnionitis. Human myometrial cells stably expressing wild-type and mutant forms of PCP4/PEP-19 were used in the evaluation of agonist-induced intracellular Ca2+ mobilization. Results: Compared to other CaM regulatory proteins, PCP4/PEP-19 transcripts were more abundant in human myometrium. The expression of PCP4/PEP-19 was lowest in myometrium of women with preterm pregnancy and chorioamnionitis. In the mouse uterus, pcp4/pep-19 expression was lower in late compared to mid-gestation and decreased in mice injected intra-amniotic with Ureaplasma parvum. In myometrial smooth muscle cells, tumor necrosis factor alpha and progesterone decreased and PCP4/PEP-19 promoter activity increased. Finally, the overexpression of PCP4/PEP-19 reduced agonist-induced intracellular Ca2+ levels in myometrial cells. Conclusion: The decreased expression of PCP4/PEP-19 in myometrium contributes to a loss of quiescence in response to infection-induced inflammation at preterm pregnancy.

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“…In Ca 2+ and Na + transmembrane channels, Ca 2+ -free CaM often associates via IQ motifs that are located in a cytoplasmic C-terminal domain [7,37]. Such interactions are important as these are known to localize this regulatory protein and also modulate its affinity for Ca 2+ [38,39]. Therefore, we have also investigated the interaction between Ca 2+free CaM and the cytoplasmic C-terminal domain of AQP4.…”

Section: Binding To Apo-calmodulinmentioning

confidence: 99%

Simultaneous binding of the N- and C-terminal cytoplasmic domains of aquaporin 4 to calmodulin

Ishida

Vogel

Conner

et al. 2022

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Aquaporin 4 (AQP4) is a water transporting, transmembrane channel protein that has important regulatory roles in maintaining cellular water homeostasis. Several other AQP proteins exhibit calmodulin (CaM)-binding properties, and CaM has recently been implicated in the cell surface localization of AQP4 that occurs in response to osmotically-driven changes in cell swelling in the central nervous system. The objective of the present study was to assess the CaM-binding properties of AQP4 in detail. Inspection of AQP4 revealed two putative CaM-binding domains (CBDs) in the cytoplasmic N-and C-terminal regions, respectively. The Ca 2+ -dependent CaMbinding properties of synthetic and recombinant AQP4 CBD peptides were assessed using fluorescence spectroscopy, isothermal titration calorimetry, and two-dimensional 1 H, 15 N-HSQC NMR with 15 N-labeled CaM. The N-terminal CBD peptide of AQP4 predominantly interacted with the N-lobe of CaM with a 1:1 binding ratio and a Kd of 3.4 µM. CaM bound two C-terminal AQP4 peptides with interactions observed for both the C-and N-lobes of CaM (Kd1: 3.6 µM, Kd2: 113.6 µM, respectively). A recombinant AQP4 protein domain (rAQP4ct, containing the entire cytosolic C-terminal domain sequence) bound CaM in a 1:1 binding mode with a Kd of 6.1 µM. A ternary bridging complex could be generated with the N-and C-lobes of CaM interacting simultaneously with the N-and C-terminal CBD peptides. These data suggest that this unique adapter protein binding mode of CaM and AQP4 may be an important regulatory mechanism for the vesicular trafficking of AQP4.

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PEP-19 modulates calcium binding to calmodulin by electrostatic steering

Cited by 22 publications

References 43 publications

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Expression, Regulation, and Function of the Calmodulin Accessory Protein PCP4/PEP-19 in Myometrium

Simultaneous binding of the N- and C-terminal cytoplasmic domains of aquaporin 4 to calmodulin

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