Calsequestrin

{{Short description|Calcium-binding protein}} {{infobox protein | Name = calsequestrin 1 (fast-twitch, skeletal muscle) | caption = Calsequestrin monomer showing the three repeating calsequestrin domains | image = Calsequestrin1.png | width = | HGNCid = 1512 | Symbol = CASQ1 | AltSymbols = CASQ | EntrezGene = 844 | OMIM = 114250 | RefSeq = NM_001231 | UniProt = P31415 | PDB = 1A8Y | ECnumber = | Chromosome = 1 | Arm = q | Band = 21 | LocusSupplementaryData = }} {{infobox protein | Name = calsequestrin 2 (cardiac muscle) | caption = | image = | width = | HGNCid = 1513 | Symbol = CASQ2 | AltSymbols = | EntrezGene = 845 | OMIM = 114251 | RefSeq = NM_001232 | UniProt = O14958 | PDB = | ECnumber = | Chromosome = 1 | Arm = p | Band = 13.3 | LocusSupplementaryData = -p11 }} {{Infobox protein family | Symbol = Calsequestrin | Name = Calsequestrin | image = PDB 1a8y EBI.jpg | width = | caption = crystal structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum at 2.4 a resolution | Pfam = PF01216 | Pfam_clan = CL0172 | InterPro = IPR001393 | SMART = | PROSITE = PDOC00675 | MEROPS = | SCOP = 1a8y | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} '''Calsequestrin''' is a calcium-binding protein that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also helps the sarcoplasmic reticulum store an extraordinarily high amount of calcium ions. Each molecule of calsequestrin can bind 18 to 50 Ca2+ ions.<ref>{{cite book | page=192 | last=Katz | first=Arnold M. | title=Physiology of the Heart | edition=4th | publisher=Lippincott Williams & Wilkins | year=2005 | isbn=978-0-7817-5501-6 }}</ref> Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface. Two forms of calsequestrin have been identified. The cardiac form Calsequestrin-2 (CASQ2) is present in cardiac and slow skeletal muscle and the fast skeletal form Calsequestrin-1(CASQ1) is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation.<ref name="pmid3427023">{{cite journal | vauthors = Slupsky JR, Ohnishi M, Carpenter MR, Reithmeier RA | title = Characterization of cardiac calsequestrin | journal = Biochemistry | volume = 26 | issue = 20 | pages = 6539–44 |date=October 1987 | pmid = 3427023 | doi = 10.1021/bi00394a038}}</ref> When calcium binds there is a structural change whereby the alpha-helical content of the protein increases from 3 to 11%.<ref name="pmid3427023" /> Both forms of calsequestrin are phosphorylated by casein kinase 2, but the cardiac form is phosphorylated more rapidly and to a higher degree.<ref name="pmid1985907">{{cite journal | vauthors = Cala SE, Jones LR | title = Phosphorylation of cardiac and skeletal muscle calsequestrin isoforms by casein kinase II. Demonstration of a cluster of unique rapidly phosphorylated sites in cardiac calsequestrin | journal = J. Biol. Chem. | volume = 266 | issue = 1 | pages = 391–8 |date=January 1991 | doi = 10.1016/S0021-9258(18)52447-9 | pmid = 1985907 | doi-access = free }}</ref> Calsequestrin is also secreted in the gut where it deprives bacteria of calcium ions.<ref>{{Cite journal |last1=NováK |first1=P. |last2=Soukup |first2=T. |date=2011-06-30 |title=Calsequestrin Distribution, Structure and Function, Its Role in Normal and Pathological Situations and the Effect of Thyroid Hormones |url=https://www.biomed.cas.cz/physiolres/pdf/60/60_439.pdf |journal=Physiological Research |volume=60 |issue=3 |language=en |pages=439–452 |doi=10.33549/physiolres.931989 |pmid=21401301 |issn=1802-9973}}</ref>

== Cardiac calsequestrin == Cardiac calsequestrin (CASQ2) plays an integral role in cardiac regulation. Mutations in the cardiac calsequestrin gene have been associated with cardiac arrhythmia and sudden death.<ref name=":0">{{Cite journal|last=Gryoke|first=Sandor|year=2003|title=Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=100|issue=20|pages=11759–11764|doi=10.1073/pnas.1932318100|pmid=13130076|pmc=208831|bibcode=2003PNAS..10011759T|doi-access=free}}</ref> CASQ2 is thought to have a role in regulating cardiac excitation-contraction coupling and calcium-induced calcium release (CICR) in the heart, as overexpression of CASQ2 has been shown to substantially raise the magnitude of cell-averaged ICA-induced calcium transients and spontaneous calcium sparks in isolated heart cells.<ref name=":0" /> Furthermore, CASQ2 modulates the CICR mechanism by lengthening to process to functionally recharge the sarcoplasmic reticulum's calcium ion stores.<ref name=":0" /> A lack of or mutation in CASQ2 has been directly associated with catecholaminergic polymorphic ventricular tachycardia (CPVT).<ref name=":1">{{Cite journal|last1=Kim|first1=EunJung|last2=Youn|first2=Buhyun|last3=Kemper|first3=Lenord|last4=Campbell|first4=Cait|last5=Milting|first5=Hendrik|last6=Varsanyi|first6=Magdolna|last7=Kang|first7=ChulHee|date=2007-11-02|title=Characterization of Human Cardiac Calsequestrin and its Deleterious Mutants|journal=Journal of Molecular Biology|volume=373|issue=4|pages=1047–1057|doi=10.1016/j.jmb.2007.08.055|pmid=17881003}}</ref> A mutation can have a significant effect if it disrupts the linear polymerization ability of CASQ2, which directly accounts for its high-capacity to bind Ca2+.<ref name=":1" /> In addition, the hydrophobic core of domain II appears to be necessary for CASQ2's function, because a single amino acid mutation that disrupts this hydrophobic core directly leads to molecular aggregates, which are unable to respond to calcium ions.<ref name=":1" />

==References== {{reflist}}

==Further reading== * {{cite journal |vauthors=Wang S, Trumble WR, Liao H, Wesson CR, Dunker AK, Kang CH |title=Crystal structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum |journal=Nat. Struct. Biol. |volume=5 |issue=6 |pages=476–83 |year=1998 |pmid=9628486 |doi=10.1038/nsb0698-476|s2cid=7967757 }}

==External links== * [https://www.ncbi.nlm.nih.gov/books/NBK1289/ GeneReviews/NCBI/NIH/UW entry on Catecholaminergic Polymorphic Ventricular Tachycardia] * {{MeshName|Calsequestrin}}

Category:Protein families Category:Endoplasmic reticulum resident proteins