Structural insights into binding of STAC proteins to voltage-gated calcium channels

Yuen, Siobhan M. Wong King; Campiglio, Marta; Tung, Ching‐Chieh; Flucher, Bernhard E.; Petegem, Filip Van

doi:10.1073/pnas.1708852114

Cited by 59 publications

(132 citation statements)

References 38 publications

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“…Indeed, in a recent X-ray analysis study, we solved the structure of tandem-SH3 domains of STAC in complex with the II-III loop of Ca V 1.1. Introducing the NAM mutation in the SH3-1 domain or mutations in the corresponding binding site of the II-III loop both abolished the interaction and impaired EC coupling (6). However, we and others previously showed that the NAM mutation in STAC3 did not prevent STAC3-Ca V 1.1 association in skeletal myotubes (2-4, 7).…”

Section: Discussionmentioning

confidence: 74%

“…First, while we demonstrated that STAC3 interacts with Ca V 1.1 as stably as the β 1a subunit (7), the measured affinity of the STAC SH3-1/II-III loop interaction is more than 100-fold weaker, suggesting that this site alone would not be sufficient for a stable interaction (6). Second, the four IQ residues critical for the STAC interaction are conserved among the IQ domains of Ca V 1.1 and Ca V 1.2, and mutation of three residues not conserved between these two isoforms did not weaken the STAC3/ Ca V 1.2 complex (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, CDI of Ca V 1.2 can be abolished by a truncated STAC3 containing the C1 domain but lacking the SH3 domains (6). Thus, it is likely that the C1 domain in STAC proteins and the IQ domain in Ca V 1 channels are the corresponding sites responsible for the association of STAC with the channel complex in the triads and for interference with CDI.…”

Section: Discussionmentioning

confidence: 99%

“…Using X-ray crystallography, we recently identified the II-III loop of Ca V 1 channels as the SH3-1 binding domain. Mutation of the three amino acids of Ca V 1.1 critical for this interaction resulted in impaired EC coupling, similarly to the effects of introducing the NAM mutation in the SH3-1 domain (6). However, the molecular domain of Ca V 1 channels responsible for the interaction with the C1 domain of STAC proteins remained to be discovered.…”

mentioning

confidence: 97%

“…All three STAC proteins contain one C1 domain and two SH3 protein interaction domains (6). We previously demonstrated that the stable association of STAC3 to the Ca V 1 channel complex in the triads of skeletal muscle relies on the C1 domain (7).…”

mentioning

confidence: 99%

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STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

Campiglio

Bagneaux

Ortner

et al. 2018

Biophysical Journal

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The adaptor proteins STAC1, STAC2, and STAC3 represent a newly identified family of regulators of voltage-gated calcium channel (Ca V ) trafficking and function. The skeletal muscle isoform STAC3 is essential for excitation-contraction coupling and its mutation causes severe muscle disease. Recently, two distinct molecular domains in STAC3 were identified, necessary for its functional interaction with Ca V 1.1: the C1 domain, which recruits STAC proteins to the calcium channel complex in skeletal muscle triads, and the SH3-1 domain, involved in excitation-contraction coupling. These interaction sites are conserved in the three STAC proteins. However, the molecular domain in Ca V 1 channels interacting with the STAC C1 domain and the possible role of this interaction in neuronal Ca V 1 channels remained unknown. Using Ca V 1.2/2.1 chimeras expressed in dysgenic (Ca V 1.1) myotubes, we identified the amino acids 1,641-1,668 in the C terminus of Ca V 1.2 as necessary for association of STAC proteins. This sequence contains the IQ domain and alanine mutagenesis revealed that the amino acids important for STAC association overlap with those making contacts with the C-lobe of calcium-calmodulin (Ca/CaM) and mediating calcium-dependent inactivation of Ca V 1.2. Indeed, patch-clamp analysis demonstrated that coexpression of either one of the three STAC proteins with Ca V 1.2 opposed calcium-dependent inactivation, although to different degrees, and that substitution of the Ca V 1.2 IQ domain with that of Ca V 2.1, which does not interact with STAC, abolished this effect. These results suggest that STAC proteins associate with the Ca V 1.2 C terminus at the IQ domain and thus inhibit calcium-dependent feedback regulation of Ca V 1.2 currents.ecently STAC3 (SH3 and cysteine-rich containing protein 3) has been identified as an essential regulator of calcium channel trafficking and function in skeletal muscle excitationcontraction (EC) coupling and a mutation in STAC3 has been linked to the severe muscle disease Native American myopathy (NAM) (1, 2). Expression of STAC3 is restricted to skeletal muscle, where STAC3 associates with the voltage-gated calcium channel Ca V 1.1 and is involved in mediating voltage-induced calcium release from the sarcoplasmic reticulum (3, 4). In nonmuscle cells, STAC3 was shown to facilitate functional membrane expression of Ca V 1.1 and alter the current properties of Ca V 1.2 (5), suggesting a role of STAC proteins as an L-type calcium channel (Ca V 1) regulator. STAC3 belongs to a family of adaptor proteins that comprises two additional isoforms, STAC1 and STAC2, which are highly expressed in the brain (1).All three STAC proteins contain one C1 domain and two SH3 protein interaction domains (6). We previously demonstrated that the stable association of STAC3 to the Ca V 1 channel complex in the triads of skeletal muscle relies on the C1 domain (7). In contrast, the NAM mutation, which impairs EC coupling and is located in the SH3-1 domain of STAC3 (2-4), did not abolish the interaction with ...

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

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STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

Campiglio

Bagneaux

Ortner

et al. 2018

Biophysical Journal

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STAC3variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

et al. 2018

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SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca release. Co-immunoprecipitation of STAC3 with Ca 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and Ca 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of Ca 1.1 sarcolemma mislocalization or impaired STAC3-Ca 1.1 interaction.

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STAC3 incorporation into skeletal muscle triads occurs independent of the dihydropyridine receptor

Campiglio

Kaplan

Flucher

2018

Journal Cellular Physiology

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Excitation-contraction (EC) coupling in skeletal muscles operates through a physical interaction between the dihydropyridine receptor (DHPR), acting as a voltage sensor, and the ryanodine receptor (RyR1), acting as a calcium release channel. Recently, the adaptor protein SH3 and cysteine-rich containing protein 3 (STAC3) has been identified as a myopathy disease gene and as an additional essential EC coupling component. STAC3 interacts with DHPR sequences including the critical EC coupling domain and has been proposed to function in linking the DHPR and RyR1. However, we and others demonstrated that incorporation of recombinant STAC3 into skeletal muscle triads critically depends only on the DHPR but not the RyR1. On the contrary, here, we provide evidence that endogenous STAC3 incorporates into triads in the absence of the DHPR in myotubes and muscle fibers of dysgenic mice. This finding demonstrates that STAC3 interacts with additional triad proteins and is consistent with its proposed role in directly or indirectly linking the DHPR with the RyR1.

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Structural insights into binding of STAC proteins to voltage-gated calcium channels

Cited by 59 publications

References 38 publications

STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

STAC Proteins Associate to the IQ Domain of CaV1.2 and Inhibit Calcium-Dependent Inactivation

STAC3variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

STAC3 incorporation into skeletal muscle triads occurs independent of the dihydropyridine receptor

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