NaV1.2 EFL domain allosterically enhances Ca2+ binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD

Mahling, Ryan; Hovey, Liam; Isbell, Holly M.; Marx, Dagan C.; Miller, Mark S.; Kilpatrick, Adina M.; Weaver, Lisa D.; Yoder, Jesse; Kim, Elaine H.; Andresen, Corinne; Li, Shuxiang; Shea, Madeline A.

doi:10.1016/j.str.2021.03.002

Cited by 4 publications

(3 citation statements)

References 140 publications

(178 reference statements)

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“…In this study, we demonstrated p.N138K decreases Ca 2+ -binding affinity, but the degree was not as much as that of p.D130G in literature. 8,27 This result well reflects the different effect of 2 variants on CaM structure. Of course we cannot exclude that in vivo the p.N138K defect could be rescued by some target proteins such as kinases and other channels regulated by CaM.…”

Section: Discussionsupporting

confidence: 60%

Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family

Kato

Isbell

Fressart

et al. 2022

Circ: Arrhythmia and Electrophysiology

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Background: CaM (calmodulin), encoded by 3 separate genes ( CALM1 , CALM2 , and CALM3 ), is a multifunctional Ca 2+ -binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo. We identified a novel CALM3 variant, p.Asn138Lys (N138K), in a 4-generation family segregating with LQTS. The aim of this study was to elucidate its pathogenicity and to compare it with that of p.D130G-CaM—a variant associated with a severe LQTS phenotype. Methods: We performed whole exome sequencing for a large, 4-generation family affected by LQTS. To assess the effect of the detected CALM3 variant, the intrinsic Ca 2+ -binding affinity was measured by stoichiometric Ca 2+ titrations and equilibrium titrations. L-type Ca 2+ and slow delayed rectifier potassium currents (I CaL and I Ks ) were recorded by whole-cell patch-clamp. Cav1.2 and Kv7.1 membrane expression were determined by optical fluorescence assays. Results: We identified 14 p.N138K-CaM carriers in a family where 2 sudden deaths occurred in children. Several members were only mildly affected compared with CaM-LQTS patients to date described in literature. The intrinsic Ca 2+ -binding affinity of the CaM C-terminal domain was 10-fold lower for p.N138K-CaM compared with WT-CaM. I CaL inactivation was slowed in cells expressing p.N138K-CaM but less than in p.D130G-CaM cells. Unexpectedly, a larger I Ks current density was observed in cells expressing p.N138K-CaM, but not for p.D130G-CaM, compared with WT-CaM. Conclusions: The p.N138K CALM3 variant impairs Ca 2+ -binding affinity of CaM and I CaL inactivation but potentiates I Ks . The variably expressed phenotype of this variant compared with previously published de novo LQTS-CaM variants is likely explained by a milder impairment of I CaL inactivation combined with I Ks augmentation.

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Section: Discussionsupporting

confidence: 60%

Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family

Kato

Isbell

Fressart

et al. 2022

Circ: Arrhythmia and Electrophysiology

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“…Although there is a Ca 2+ -binding EFL motif upstream of the IQ domain in the Na v 1.2 channel, the Ca 2+ -mediated changes in modification of Na v 1.2 function are proposed to be likely from the interaction between CaM and Na v 1.2 IQ domain when Ca 2+ binding to CaM. The Na v 1.2 channel EFL motif was indicated to enhance Ca 2+ binding to CaM interacting with the channel [41].…”

Section: Na V 12mentioning

confidence: 96%

Calmodulin Interactions with Voltage-Gated Sodium Channels

Luan

2021

IJMS

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Calmodulin (CaM) is a small protein that acts as a ubiquitous signal transducer and regulates neuronal plasticity, muscle contraction, and immune response. It interacts with ion channels and plays regulatory roles in cellular electrophysiology. CaM modulates the voltage-gated sodium channel gating process, alters sodium current density, and regulates sodium channel protein trafficking and expression. Many mutations in the CaM-binding IQ domain give rise to diseases including epilepsy, autism, and arrhythmias by interfering with CaM interaction with the channel. In the present review, we discuss CaM interactions with the voltage-gated sodium channel and modulators involved in CaM regulation, as well as summarize CaM-binding IQ domain mutations associated with human diseases in the voltage-gated sodium channel family.

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“…For example, the binding of calmodulin (CaM) to the C‐terminal domain of the neuronal voltage‐gated sodium channel Na V 1.2 regulates the channel activity and inactivation, which are crucial for the initiation and propagation of action potentials in neurons 6 . Mahling et al 7 showed that human Na V 1.2 bound tightly to apo CaM whereas bound Ca 2+ reduced the affinity in the CaM‐binding sites. Shihoya et al 8 reported that the endothelin 1 (ET‐1)‐endothelin receptor (ET B ) complex has a large interacting surface area, which accounts for the exceptionally high affinity for ET‐1 with K d on the sub‐nanomolar order.…”

Section: Introductionmentioning

confidence: 99%

MPA‐Pred: A machine learning approach for predicting the binding affinity of membrane protein–protein complexes

Ridha,

Gromiha

2023

Proteins

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Membrane protein–protein interactions are essential for several functions including cell signaling, ion transport, and enzymatic activity. These interactions are mainly dictated by their binding affinities. Although several methods are available for predicting the binding affinity of protein–protein complexes, there exists no specific method for membrane protein–protein complexes. In this work, we collected the experimental binding affinity data for a set of 114 membrane protein–protein complexes and derived several structure and sequence‐based features. Our analysis on the relationship between binding affinity and the features revealed that the important factors mainly depend on the type of membrane protein and the functional class of the protein. Specifically, aromatic and charged residues at the interface, and aromatic‐aromatic and electrostatic interactions are found to be important to understand the binding affinity. Further, we developed a method, MPA‐Pred, for predicting the binding affinity of membrane protein–protein complexes using a machine learning approach. It showed an average correlation and mean absolute error of 0.83 and 0.91 kcal/mol, respectively, using the jack‐knife test on a set of 114 complexes. We have also developed a web server and it is available at https://web.iitm.ac.in/bioinfo2/MPA-Pred/. This method can be used for predicting the affinity of membrane protein–protein complexes at a large scale and aid to improve drug design strategies.

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NaV1.2 EFL domain allosterically enhances Ca2+ binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD

Cited by 4 publications

References 140 publications

Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family

Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family

Calmodulin Interactions with Voltage-Gated Sodium Channels

MPA‐Pred: A machine learning approach for predicting the binding affinity of membrane protein–protein complexes

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