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dc.contributor.authorNiu, J.
dc.contributor.authorDick, I.E.
dc.contributor.authorYang, W.
dc.date.accessioned2019-05-21T18:56:25Z
dc.date.available2019-05-21T18:56:25Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85055617349&doi=10.7554%2feLife.35222&partnerID=40&md5=3fe5951e47b58e113f8c68a76b9ac122
dc.identifier.urihttp://hdl.handle.net/10713/9293
dc.description.abstractCalmodulin (CaM) serves as a pervasive regulatory subunit of Ca V 1, Ca V 2, and Na V 1 channels, exploiting a functionally conserved carboxy-tail element to afford dynamic Ca 2+ -feedback of cellular excitability in neurons and cardiomyocytes. Yet this modularity counters functional adaptability, as global changes in ambient CaM indiscriminately alter its targets. Here, we demonstrate that two structurally unrelated proteins, SH3 and cysteine-rich domain (stac) and fibroblast growth factor homologous factors (fhf) selectively diminish Ca 2+ /CaM-regulation of Ca V 1 and Na V 1 families, respectively. The two proteins operate on allosteric sites within upstream portions of respective channel carboxy-tails, distinct from the CaM-binding interface. Generalizing this mechanism, insertion of a short RxxK binding motif into Ca V 1.3 carboxy-tail confers synthetic switching of CaM regulation by Mona SH3 domain. Overall, our findings identify a general class of auxiliary proteins that modify Ca 2+ /CaM signaling to individual targets allowing spatial and temporal orchestration of feedback, and outline strategies for engineering Ca 2+ /CaM signaling to individual targets. Copyright Niu et al.en_US
dc.description.sponsorshipThis work was supported by grants from NINDS (DTY, IED, TI), NIMH (DTY, MBJ), NHLBI (GFT) and NSF (JN).en_US
dc.description.urihttps://dx.doi.org/10.7554/eLife.35222en_US
dc.language.isoen_USen_US
dc.publishereLife Sciences Publications Ltden_US
dc.relation.ispartofeLife
dc.subject.meshAllosteric Regulationen_US
dc.subject.meshCalcium Channelsen_US
dc.subject.meshVoltage-Gated Sodium Channelsen_US
dc.titleAllosteric regulators selectively prevent Ca2+-feedback of CaV and NaV channelsen_US
dc.typeArticleen_US
dc.identifier.doi10.7554/eLife.35222
dc.identifier.pmid30198845


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