The Calmodulin Regulator Protein, PEP-19, Sensitizes ATP-induced Ca2+ Release

Wang, Xu; Xiong, Liang Wen; Ayadi, Amina El; Boehning, Darren; Putkey, John A.

doi:10.1074/jbc.m112.411314

Cited by 14 publications

(20 citation statements)

References 46 publications

(47 reference statements)

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“…We showed previously that replacing Pro37 with Gly (PEP(P37G)) greatly inhibits the ability of PEP-19 modulate Ca 2+ binding to CaM, and to sensitize HeLa cells to ATP-dependent Ca 2+ release17. Figure 4a shows that Pro37 terminates the helical segment of PEP-19, and intramolecular NOEs show that Pro37 and Ala36 interact with neighbouring residues to stabilize the transition between helical and coiled segments in PEP-19.…”

Section: Resultsmentioning

confidence: 95%

“…We focused on the apo state since increasing the rate of Ca 2+ binding to apo CaM by PEP-19 has the potential to regulate the temporal binding of CaM to a wide spectrum of Ca 2+ -dependent target proteins. Structural features of the acidic sequence of PEP-19 were of special interests since it is necessary to both modulate Ca 2+ binding to CaM and to sensitize HeLa cells to ATP-dependent Ca 2+ release17.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PEP-19 has anti-apoptotic activity when expressed in PC12 and HEK293T cells1516, and it provides protection against Ca 2+ overload in cortical neurons16. Finally, PEP-19 sensitizes HeLa cells to ATP-dependent Ca 2+ release17.…”

mentioning

confidence: 99%

“…Moreover, the acidic sequence is required for PEP-19 to sensitize HeLa cells to ATP-dependent Ca 2+ release. Deleting or mutating the acidic sequence by, for example, converting Pro37 to Gly (PEP(P37G)) does not prevent PEP-19 from binding to CaM, but greatly decreases its ability to both modulate Ca 2+ binding to C-domain of CaM and to sensitize HeLa cells to ATP-induced Ca 2+ release17. This demonstrates that simply binding to CaM does not account for all the biological activities of PEP-19, and that tuning Ca 2+ binding to CaM via the cooperative properties of its acidic sequence and IQ motif is an important mechanism by which PEP-19 impacts at least some CaM signalling pathways.…”

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confidence: 99%

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PEP-19 modulates calcium binding to calmodulin by electrostatic steering

Wang

Putkey

2016

Nat Commun

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PEP-19 is a small protein that increases the rates of Ca2+ binding to the C-domain of calmodulin (CaM) by an unknown mechanism. Although an IQ motif promotes binding to CaM, an acidic sequence in PEP-19 is required to modulate Ca2+ binding and to sensitize HeLa cells to ATP-induced Ca2+ release. Here, we report the NMR solution structure of a complex between PEP-19 and the C-domain of apo CaM. The acidic sequence of PEP-19 associates between helices E and F of CaM via hydrophobic interactions. This allows the acidic side chains in PEP-19 to extend toward the solvent and form a negatively charged surface that resembles a catcher's mitt near Ca2+ binding loop III of CaM. The topology and gradients of negative electrostatic surface potential support a mechanism by which PEP-19 increases the rate of Ca2+ binding to the C-domain of CaM by ‘catching' and electrostatically steering Ca2+ to site III.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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PEP-19 modulates calcium binding to calmodulin by electrostatic steering

Wang

Putkey

2016

Nat Commun

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“…The coexpression changes of Gap43 and Pcp4 may couple the synthetic events that accompany the regeneration of SGNs [49] . Both may also have a role to play in calmodulin and calcium availability [50] . Nptx2 (Narp) encodes for the neuron-specific protein pentraxin (NPTX2, NP2); it was found to be increased following hypoxia/ischemia in neonatal brain [51] .…”

Section: Expression Of Neuronal Growth-associated Genesmentioning

confidence: 99%

Expression of nestin-associated genes in the inner ear of newborn rats following injury and hypoxia

Gross

Mazurek

2015

Inflamm Cell Signal

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We used organotypic cultures of the stria vascularis (SV), the organ of Corti (OC) and the modiolus (MOD) of newborn rats to analyze the differential expression levels and responses of cytoskeletal, myelin-and neural growth factor-associated genes following preparatory injury and hypoxia. The transcript mRNA levels of the neurofilaments Nefl, Nefm, the microtubule-associated proteins Mapt, Map1a, Map2, and of the myelin basic protein Mbp decrease during 24 h in a coordinated way across the MOD and OC regions. The increased cell death rate in the MOD region is associated with an increased expression of Nes, the transcript encoding the intermediate filament nestin, and of the neural growth factor receptor Ngfr, the growth-associated protein 43 Gap43 and the Purkinje cell protein Pcp4. The correlation analysis revealed close associations between Nes expression and genes involved in apoptotic and necrotic cell death (caspase Casp3, calpains Capn1, Capn2, Capns1), the glutamate pathway (glutamate receptor NMDA associated protein 1 Grina, glial high affinity glutamate transporter Slc1a3), cytoskeletal genes (Nefm, Map2, Map1a, Mbp), transcription factors (hypoxia inducible factor Hif-1a, jun proto-oncogene Jun, brain expressed myelocytomatosis B-myc, HES family bHLH transcription factor 1 Hes-1, forkhead-box D3 Foxd3) and neural growth factors (Ngfr, Gap43 and Pcp4). The unique response and the composition of the Nes cluster made us conclude that the expression of cell-death-associated genes and the regeneration-associated genes takes place in a coordinated way, and differs between the MOD and the OC/SV regions.

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Screening and validation of plasma cell-derived, purinergic, and calcium signalling-related genetic signature to predict prognosis and PD-L1/PD-1 blockade responses in lung adenocarcinoma

Huang

Fan

et al. 2023

J Cancer Res Clin Oncol

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The Calmodulin Regulator Protein, PEP-19, Sensitizes ATP-induced Ca2+ Release

Cited by 14 publications

References 46 publications

PEP-19 modulates calcium binding to calmodulin by electrostatic steering

PEP-19 modulates calcium binding to calmodulin by electrostatic steering

Expression of nestin-associated genes in the inner ear of newborn rats following injury and hypoxia

Screening and validation of plasma cell-derived, purinergic, and calcium signalling-related genetic signature to predict prognosis and PD-L1/PD-1 blockade responses in lung adenocarcinoma

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