Three residues in the luminal domain of triadin impact on Trisk 95 activation of skeletal muscle ryanodine receptors

Elize Wium, Angela F. Dulhunty, Nicole BEARD

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Triadin isoforms, splice variants of one gene, maintain healthy Ca2+ homeostasis in skeletal muscle by subserving several functions including an influence on Ca2+ release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200–232. Selective alanine substitutions show that K218, K220, and K224 together facilitate normal Trisk 95 binding to RyR1 and channel activation. Neither RyR1 binding nor activation are altered by alanine substitution of K220 alone or of K218 and K224. Therefore K218, K220, and K224 contribute to a robust binding and activation site that is disrupted only when the charge on all three residues is neutralized. We suggest that charged pair interactions between acidic RyR1 residues D4878, D4907, and E4908 and Trisk 95 residues K218, K220, and K224 facilitate Trisk 95 binding to RyR1 and channel activation. Since K218, K220, and K224 are also required for CSQ binding to RyRs (Kobayashi et al. 17, J Biol Chem 275, 17639–17646), the results suggest that Trisk 95 may not simultaneously bind to RyR1 and CSQ, contrary to the widely held belief that triadin monomers form a quaternary complex with junctin, CSQ and RyR1. Therefore, the in vivo role of triadin monomers in modulating RyR1 activity is likely unrelated to CSQ.
Original languageEnglish
Pages (from-to)1985-1994
Number of pages10
JournalPflugers Archiv
Volume468
Issue number11-12
DOIs
Publication statusPublished - Nov 2016

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Ryanodine Receptor Calcium Release Channel
Muscle
Skeletal Muscle
Chemical activation
Ion Channels
Alanine
Protein Isoforms
triadin
Substitution reactions
Monomers
Amino Acids
Homeostasis
Genes
Binding Sites
Ligands

Cite this

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title = "Three residues in the luminal domain of triadin impact on Trisk 95 activation of skeletal muscle ryanodine receptors",
abstract = "Triadin isoforms, splice variants of one gene, maintain healthy Ca2+ homeostasis in skeletal muscle by subserving several functions including an influence on Ca2+ release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200–232. Selective alanine substitutions show that K218, K220, and K224 together facilitate normal Trisk 95 binding to RyR1 and channel activation. Neither RyR1 binding nor activation are altered by alanine substitution of K220 alone or of K218 and K224. Therefore K218, K220, and K224 contribute to a robust binding and activation site that is disrupted only when the charge on all three residues is neutralized. We suggest that charged pair interactions between acidic RyR1 residues D4878, D4907, and E4908 and Trisk 95 residues K218, K220, and K224 facilitate Trisk 95 binding to RyR1 and channel activation. Since K218, K220, and K224 are also required for CSQ binding to RyRs (Kobayashi et al. 17, J Biol Chem 275, 17639–17646), the results suggest that Trisk 95 may not simultaneously bind to RyR1 and CSQ, contrary to the widely held belief that triadin monomers form a quaternary complex with junctin, CSQ and RyR1. Therefore, the in vivo role of triadin monomers in modulating RyR1 activity is likely unrelated to CSQ.",
keywords = "Calcium signaling, Ryanodine receptor calcium release channels, Skeletal muscle, Triadin",
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Three residues in the luminal domain of triadin impact on Trisk 95 activation of skeletal muscle ryanodine receptors. / Wium, Elize; Dulhunty, Angela F.; BEARD, Nicole.

In: Pflugers Archiv, Vol. 468, No. 11-12, 11.2016, p. 1985-1994.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Three residues in the luminal domain of triadin impact on Trisk 95 activation of skeletal muscle ryanodine receptors

AU - Wium, Elize

AU - Dulhunty, Angela F.

AU - BEARD, Nicole

PY - 2016/11

Y1 - 2016/11

N2 - Triadin isoforms, splice variants of one gene, maintain healthy Ca2+ homeostasis in skeletal muscle by subserving several functions including an influence on Ca2+ release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200–232. Selective alanine substitutions show that K218, K220, and K224 together facilitate normal Trisk 95 binding to RyR1 and channel activation. Neither RyR1 binding nor activation are altered by alanine substitution of K220 alone or of K218 and K224. Therefore K218, K220, and K224 contribute to a robust binding and activation site that is disrupted only when the charge on all three residues is neutralized. We suggest that charged pair interactions between acidic RyR1 residues D4878, D4907, and E4908 and Trisk 95 residues K218, K220, and K224 facilitate Trisk 95 binding to RyR1 and channel activation. Since K218, K220, and K224 are also required for CSQ binding to RyRs (Kobayashi et al. 17, J Biol Chem 275, 17639–17646), the results suggest that Trisk 95 may not simultaneously bind to RyR1 and CSQ, contrary to the widely held belief that triadin monomers form a quaternary complex with junctin, CSQ and RyR1. Therefore, the in vivo role of triadin monomers in modulating RyR1 activity is likely unrelated to CSQ.

AB - Triadin isoforms, splice variants of one gene, maintain healthy Ca2+ homeostasis in skeletal muscle by subserving several functions including an influence on Ca2+ release through the ligand-gated ryanodine receptor (RyR1) ion channels. The predominant triadin isoform in skeletal muscle, Trisk 95, activates RyR1 in vitro via binding to previously unidentified amino acids between residues 200 and 232. Here, we identify three amino acids that influence Trisk 95 binding to RyR1 and ion channel activation, using peptides encompassing residues 200–232. Selective alanine substitutions show that K218, K220, and K224 together facilitate normal Trisk 95 binding to RyR1 and channel activation. Neither RyR1 binding nor activation are altered by alanine substitution of K220 alone or of K218 and K224. Therefore K218, K220, and K224 contribute to a robust binding and activation site that is disrupted only when the charge on all three residues is neutralized. We suggest that charged pair interactions between acidic RyR1 residues D4878, D4907, and E4908 and Trisk 95 residues K218, K220, and K224 facilitate Trisk 95 binding to RyR1 and channel activation. Since K218, K220, and K224 are also required for CSQ binding to RyRs (Kobayashi et al. 17, J Biol Chem 275, 17639–17646), the results suggest that Trisk 95 may not simultaneously bind to RyR1 and CSQ, contrary to the widely held belief that triadin monomers form a quaternary complex with junctin, CSQ and RyR1. Therefore, the in vivo role of triadin monomers in modulating RyR1 activity is likely unrelated to CSQ.

KW - Calcium signaling

KW - Ryanodine receptor calcium release channels

KW - Skeletal muscle

KW - Triadin

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U2 - 10.1007/s00424-016-1869-7

DO - 10.1007/s00424-016-1869-7

M3 - Article

VL - 468

SP - 1985

EP - 1994

JO - Pflugers Archiv European Journal of Physiology

JF - Pflugers Archiv European Journal of Physiology

SN - 0031-6768

IS - 11-12

ER -