Sandbox Reserved 820: Difference between revisions

The calsequestrin 2 plays a major role here, because it helps the release of the calcium in the cytosol while the membrane depolarization occurs and traps the calcium inside the lumen of the sarcoplasmic reticulum.<ref name="CASQ2 role">NCBI Gene Ressource: CASQ2 calsequestrin 2  http://www.ncbi.nlm.nih.gov/gene/845</ref>

Each monomer is divided in <scene name='56/568018/Monomer_structure/5'>3 thioredoxin domains (TRX)</scene>: <scene name='56/568018/Monomer_structure/7'>the N-term</scene>, <scene name='56/568018/Monomer_structure/6'>the middle</scene> and the <scene name='56/568018/Monomer_structure/8'>C-term</scene> domains. Each of these has a regular structure: a <scene name='56/568018/Beta_sheet/4'>5 strands beta sheet core</scene>  surrounded by <scene name='56/568018/Alpha_helix/3'>4 alpha helices</scene>.<ref name="Martin">PMID:7788290</ref>

Finally, the C-term Asp-rich extremity  is intrisically disordered.

Inside the sarcoplasmic reticulum lumen, CASQ2 polymerizes to form <scene name='56/568018/Dimer/1'>homodimers</scene>, homotetramers and  

There are two types of dimerisation: the  

The front-to-front form is stabilized by intermolecular interactions between the  

<scene name='56/568018/Dimer/3'>α2 helix of the domain I</scene> of each CASQ2.<ref name="Crystal Structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum (Wang et al., 1998)">http://www.nature.com/nsmb/journal/v5/n6/abs/nsb0698-476.html</ref> The intermolecular salt bridges are built between <scene name='56/568018/Dimer/13'>Glu 55 and Lys 49</scene>.<ref name="Crystal Structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum (Wang et al., 1998)">http://www.nature.com/nsmb/journal/v5/n6/abs/nsb0698-476.html</ref>  This dimerisation induces the formation of an electronegative pocket which involves these amino acids: for the first CASQ2 Glu 39, Glu 54, Glu 78, Glu 92, Asp 93 and Asp 101 and for the second CASQ2 Glu 199, Asp 245, Asp 278, Glu 350 and Glu 348.<ref name="Crystal Structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum (Wang et al., 1998)">http://www.nature.com/nsmb/journal/v5/n6/abs/nsb0698-476.html</ref> <!--Mettre du VERT -->

Each monomere of CASQ2 can bind between 18 to 50 Ca²⁺. The Ca²⁺ ions bind to two or more acidic amino acids like <scene name='56/568018/Glu/2'>Glutamate</scene> or <scene name='56/568018/Asp/3'>Aspartate</scene>. These amino acids are mainly outside the CASQ2 or in the C-terminal region. It had been shown that Ca²⁺ binds to an Asp-rich region on the C-terminal domain. <!-- METTRE DU VERT MAIS LE CT N'EST PAS DISPONIBLE cf: http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2VAF&bionumber=1 -->When CASQ2 form homooligomers, Ca²⁺ can bind in the electronegative pocket due to the front-to-front form and back-to-back form.<ref name="The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca²⁺‡ and interacts with triadin (Shin et al., 2000)">The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca²⁺ and interacts with triadin (Shin et al., 2000) http://www.sciencedirect.com/science/article/pii/S0014579300022468</ref>

Ca2+ is not the only ion which can bind to the CASQ2. One of them is Mg²⁺. The affinity is for Mg²⁺ is lower than the affinity for Ca²⁺ however the number of Ca²⁺ decrease. Another ion is H⁺. When the pH is low, more H⁺ will bind to the acidic amino acids and they can not bind Ca²⁺ anymore.<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">PMID:15050380</ref>

 

== Interaction between CASQ2 and <!-- (plutôt Triadin et Junctin) -->RYR ==

CASQ2 is anchored into the membrane of SR thanks to two integral proteins: the triadin and the junctin.<ref name="Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation (Beard et Al., 2005)">PMID:15731387</ref> Triadin as well as Juctin can bind to CASQ2 because of its KEKE motif between the amino acids 210 and 224 for the triadin.<ref name="Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation (Beard et Al., 2005)">http://www.ncbi.nlm.nih.gov/pubmed/15731387</ref> The binding site of CASQ2 for the both protein is the Asp-rich region of the C-terminal region.<ref name="Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation (Beard et Al., 2005)">http://www.ncbi.nlm.nih.gov/pubmed/15731387</ref>

Triadin and Junctin interact with Ryanodin Receptor (RyR).<ref name="Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation (Beard et Al., 2005)">http://www.ncbi.nlm.nih.gov/pubmed/15731387</ref>

The binding site of CASQ2 to RyR is unknow.<ref name="Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation (Beard et Al., 2005)">http://www.ncbi.nlm.nih.gov/pubmed/15731387</ref>

 

When CASQ2 binds to Triadin and Junctin, it induces the inhibition of RyR and when CASQ2 unbinds Triadin and Junctin , it induces the activation of Ryr and an efflux of Ca²⁺ from the SR to the cytoplasm.<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">http://www.ncbi.nlm.nih.gov/pubmed/15050380</ref> CASQ2 is free when the concentration of Ca2+ is higher than 1 mM in the SR lumen.<ref name="Regulation of Ryanodine Receptors by Calsequestrin: Effect of High Luminal Ca2+ and Phosphorylation (Beard et Al., 2005)">http://www.ncbi.nlm.nih.gov/pubmed/15731387</ref>

== Regulation of CASQ2 ==   

CASQ2 can be phosphorylated by three different kinases: casein kinase I (CK I), casein kianse II (CK II) and ε protein kinase C1 (εPKC1).<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">http://www.ncbi.nlm.nih.gov/pubmed/15050380</ref> CK II is located in the SR and is able to phosphorylate Ser 378, Ser 382 and Ser 386. These residues are on the C-terminal domain.<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">http://www.ncbi.nlm.nih.gov/pubmed/15050380</ref> The consensus sequence recognized by CK II is Ser/Thr-X-X-Asp/Glu.<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">http://www.ncbi.nlm.nih.gov/pubmed/15050380</ref> More there are acidic residues after this consensus sequence, more the probabilty of phosphorylation increases.<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">http://www.ncbi.nlm.nih.gov/pubmed/15050380</ref>

"The phosphorylation and de-phosphorylation of CASQ2 my provide an off/on switch for CASQ2 to regulate Ca2+" <!-- A reformuler, mais bon...! --> But there is not any prove yet.<ref name="Calsequestrin and the calcium release channel of skeletal and cardiac muscle (Beard et Al., 2004)">http://www.ncbi.nlm.nih.gov/pubmed/15050380</ref>