Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation–contraction coupling

Rufenach, Britany; Petegem, Filip Van

doi:10.1016/j.jbc.2021.100874

Cited by 26 publications

(22 citation statements)

References 129 publications

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“…It is expressed almost exclusively in skeletal muscle. Along with other proteins, such as Cav1.1, RyR1, Cavβ1a, and junctophilin, STAC3 is responsible for the proper working of the skeletal muscle ECC machinery [ 8 ]. Nelson et al showed that STAC3-null mice, which are completely paralyzed, die at birth due to asphyxia [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the amino acid substitution of the STAC3 protein Trp284Ser, Phe295Leu, and Lys329Asn affects the ECC by violating the interaction with the II–III loop of Cav1.1 [ 10 ]. All of these mutant isoforms reduce the affinity to Cav1.1 and disrupt the ECC calcium transients, while the isoform with the Trp284Ser substitution has the most negative effect on binding with Cav1.1 [ 8 ] and is associated with a more severe phenotype.…”

Section: Discussionmentioning

confidence: 99%

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The First Russian Patient with Native American Myopathy

Муртазина

Демина

Chausova

et al. 2022

Genes

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Congenital myopathy associated with pathogenic variants in the STAC3 gene has long been considered native American myopathy (NAM). In 2017, the first case of a non-Amerindian patient with this myopathy was described. Here, we report the first Russian patient with NAM. The patient is a 17-year-old female with compound-heterozygous single nucleotide variants in the STAC3 gene: c.862A>T, p.(Lys288Ter) and c.93del, p.(Lys32ArgfsTer78). She has a milder phenotype than the earlier described patients. To our knowledge, this is the first case of a patient who had both nonsense and frameshift variants. It is assumed that the frameshift variant with premature stop codon lead to nonsense-mediated RNA decay. However, there are two additional coding isoforms of the STAC3 gene, which are not affected by this frameshift variant. We can speculate that these isoforms may partially carry out the function, and possibly explain the milder phenotype of our patient.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The First Russian Patient with Native American Myopathy

Муртазина

Демина

Chausova

et al. 2022

Genes

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“…SH3 and cysteine‐rich domain‐containing (STAC) proteins form a small group of adaptor proteins comprised of STAC1, STAC2, and STAC3. 1 , 2 While STAC1 and STAC2 are predominantly found in neuronal tissue, STAC3 is exclusively expressed in skeletal muscle. 3 In recent years, STAC3 has been touted as a potential “missing link” in skeletal muscle excitation‐contraction coupling (ECC), where it has been proposed to mediate the interactions between the voltage‐sensing dihydropyridine receptor (DHPR) and Ca 2+ ‐releasing ryanodine receptor 1 (RyR1).…”

Section: Introductionmentioning

confidence: 99%

“…SH3 and cysteine‐rich domain‐containing (STAC) proteins form a small group of adaptor proteins comprised of STAC1, STAC2, and STAC3 1,2 . While STAC1 and STAC2 are predominantly found in neuronal tissue, STAC3 is exclusively expressed in skeletal muscle 3 .…”

Section: Introductionmentioning

confidence: 99%

Molecular interactions of STAC proteins with skeletal muscle dihydropyridine receptor and excitation‐contraction coupling

et al. 2022

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Excitation‐contraction coupling (ECC) is the physiological process in which an electrical signal originating from the central nervous system is converted into muscle contraction. In skeletal muscle tissue, the key step in the molecular mechanism of ECC initiated by the muscle action potential is the cooperation between two Ca2+ channels, dihydropyridine receptor (DHPR; voltage‐dependent L‐type calcium channel) and ryanodine receptor 1 (RyR1). These two channels were originally postulated to communicate with each other via direct mechanical interactions; however, the molecular details of this cooperation have remained ambiguous. Recently, it has been proposed that one or more supporting proteins are in fact required for communication of DHPR with RyR1 during the ECC process. One such protein that is increasingly believed to play a role in this interaction is the SH3 and cysteine‐rich domain‐containing protein 3 (STAC3), which has been proposed to bind a cytosolic portion of the DHPR α1S subunit known as the II–III loop. In this work, we present direct evidence for an interaction between a small peptide sequence of the II–III loop and several residues within the SH3 domains of STAC3 as well as the neuronal isoform STAC2. Differences in this interaction between STAC3 and STAC2 suggest that STAC3 possesses distinct biophysical features that are potentially important for its physiological interactions with the II–III loop. Therefore, this work demonstrates an isoform‐specific interaction between STAC3 and the II–III loop of DHPR and provides novel insights into a putative molecular mechanism behind this association in the skeletal muscle ECC process.

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“…This is referred to as depolarization-induced Ca 2+ release (DICR) 2,3 . Studies with knockout animals have revealed that functional and structural interactions between Cav1.1 and RyR1 in muscle require at least three additional components, a β1a auxiliary subunit of DHPR 4,5 , the Stac3 adaptor protein 6,7,8 , and junctophilins 9 , which may form specific machinery for DICR 4,5,10 .…”

Section: Introductionmentioning

confidence: 99%

Reconstituted depolarization-induced Ca²⁺release platform for skeletal muscle disease mutation validation and drug discovery

Murayama

Kurebayashi

Numaga‐Tomita

et al. 2022

Preprint

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In skeletal muscle excitation-contraction (E-C) coupling, depolarization of the plasma membrane triggers Ca2+ release from the sarcoplasmic reticulum (SR), referred to as depolarization-induced Ca2+ release (DICR). DICR occurs via the type 1 ryanodine receptor (RyR1), which physically interacts with the dihydropyridine receptor Cav1.1 subunit in specific machinery formed with additional components. Exome sequencing has accelerated the discovery of many novel mutations in DICR machinery genes in various skeletal muscle diseases. However, functional validation is time-consuming because it must be performed in a skeletal muscle environment. Here, we describe a high-throughput platform for DICR that is reconstituted in non-muscle HEK293 cells. We demonstrate that Cav1.1 mutations implicated in malignant hyperthermia and myopathy exhibit divergent effects on DICR. We also tested several RyR1 inhibitors and DICR modulators. This high-throughput DICR platform will accelerate validation of mutations and drug discovery for skeletal muscle diseases.

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Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation–contraction coupling

Cited by 26 publications

References 129 publications

The First Russian Patient with Native American Myopathy

The First Russian Patient with Native American Myopathy

Molecular interactions of STAC proteins with skeletal muscle dihydropyridine receptor and excitation‐contraction coupling

Reconstituted depolarization-induced Ca²⁺release platform for skeletal muscle disease mutation validation and drug discovery

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Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation–contraction coupling

Cited by 26 publications

References 129 publications

The First Russian Patient with Native American Myopathy

The First Russian Patient with Native American Myopathy

Molecular interactions of STAC proteins with skeletal muscle dihydropyridine receptor and excitation‐contraction coupling

Reconstituted depolarization-induced Ca2+release platform for skeletal muscle disease mutation validation and drug discovery

Contact Info

Product

Resources

About

Reconstituted depolarization-induced Ca²⁺release platform for skeletal muscle disease mutation validation and drug discovery