O14958 (CASQ2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Calsequestrin-2

Alternative name(s):
Calsequestrin, cardiac muscle isoform

Gene names

Name:

CASQ2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	399 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle. The release of calcium bound to calsequestrin through a calcium release channel triggers muscle contraction. Binds 40 to 50 moles of calcium. Ref.5
Subunit structure	Monomer, homodimer and homooligomer. Mostly monomeric in the absence of calcium. Forms higher oligomers in a calcium-dependent manner. Dimers associate to form tetramers, that then form linear homopolymer chains. Ref.5
Subcellular location	Sarcoplasmic reticulum lumen. Note: This isoform of calsequestrin occurs in the sarcoplasmic reticulum's terminal cisternae luminal spaces of cardiac and slow skeletal muscle cells.
Involvement in disease	Defects in CASQ2 are the cause of catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) [MIM:611938]; also known as stress-induced polymorphic ventricular tachycardia (VTSIP). CPVT2 is an autosomal recessive form of arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Ref.5 Ref.6 Ref.8 Ref.9 Ref.10
Sequence similarities	Belongs to the calsequestrin family.

Ontologies

Keywords
Cellular component	Sarcoplasmic reticulum
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal
Ligand	Calcium
Molecular function	Muscle protein
PTM	Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	heart development Traceable author statement. Source: ProtInc striated muscle contraction Traceable author statement. Source: ProtInc
Cellular component	sarcoplasmic reticulum lumen Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	calcium ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

By similarity

Chain

20 – 399

380

Calsequestrin-2

PRO_0000004218

Regions

Compositional bias

356 – 399

44

Asp/Glu-rich (acidic)

Amino acid modifications

Glycosylation

335

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

33

1

R → Q in CPVT2; reduces calcium-dependent dimerization. Ref.5 Ref.10

VAR_055234

Natural variant

66

1

T → A. Ref.5 Ref.7
Corresponds to variant rs4074536 [ dbSNP | Ensembl ].

VAR_023692

Natural variant

76

1

V → M. Ref.5 Ref.7
Corresponds to variant rs10801999 [ dbSNP | Ensembl ].

VAR_023693

Natural variant

167

1

L → H in CPVT2; alters protein folding, reduces calcium-binding and calcium-dependent oligomerization, decreases sarcoplasmic reticulum Ca(2+) storing capacity and reduces the amplitude of I(Ca)-induced Ca(2+) transients and of spontaneous Ca(2+) sparks in permeabilized myocytes. Ref.5 Ref.9 Ref.10

VAR_044118

Natural variant

307

1

D → H in CPVT2; reduces calcium-binding and causes 50% decrease in calcium-dependent binding to triadin-1 and junctin. Ref.5 Ref.6 Ref.8

VAR_016075

Experimental info

Sequence conflict

67

1

Q → P in BAA23494. Ref.1

Secondary structure

1

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399

Helix Strand Turn

Details...

Beta strand

23 – 38

16

Helix

39 – 48

10

Beta strand

49 – 66

18

Helix

67 – 84

18

Beta strand

85 – 97

13

Helix

98 – 103

6

Beta strand

104 – 130

27

Helix

131 – 141

11

Beta strand

142 – 152

11

Helix

153 – 158

6

Beta strand

159 – 176

18

Helix

177 – 188

12

Beta strand

189 – 200

12

Helix

201 – 207

7

Beta strand

208 – 217

10

Beta strand

219 – 223

5

Beta strand

229 – 233

5

Helix

234 – 243

10

Beta strand

248 – 252

5

Helix

256 – 261

6

Beta strand

262 – 278

17

Helix

279 – 294

16

Beta strand

295 – 298

4

Beta strand

300 – 307

8

Helix

312 – 320

9

Beta strand

321 – 328

8

Beta strand

330 – 351

22

Helix

356 – 361

6

Beta strand

362 – 369

8

Sequences

	Sequence		Length	Mass (Da)
	O14958 [UniParc]. Last modified September 19, 2002. Version 2. Checksum: 7794DC2FF7E4B064	FASTA	399	46,436
	10 20 30 40 50 60 MKRTHLFIVG IYFLSSCRAE EGLNFPTYDG KDRVVSLSEK NFKQVLKKYD LLCLYYHEPV 70 80 90 100 110 120 SSDKVTQKQF QLKEIVLELV AQVLEHKAIG FVMVDAKKEA KLAKKLGFDE EGSLYILKGD 130 140 150 160 170 180 RTIEFDGEFA ADVLVEFLLD LIEDPVEIIS SKLEVQAFER IEDYIKLIGF FKSEDSEYYK 190 200 210 220 230 240 AFEEAAEHFQ PYIKFFATFD KGVAKKLSLK MNEVDFYEPF MDEPIAIPNK PYTEEELVEF 250 260 270 280 290 300 VKEHQRPTLR RLRPEEMFET WEDDLNGIHI VAFAEKSDPD GYEFLEILKQ VARDNTDNPD 310 320 330 340 350 360 LSILWIDPDD FPLLVAYWEK TFKIDLFRPQ IGVVNVTDAD SVWMEIPDDD DLPTAEELED 370 380 390 WIEDVLSGKI NTEDDDEDDD DDDNSDEEDN DDSDDDDDE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a human cDNA for cardiac calsequestrin and its chromosomal assignment to 1p13.3 by fluorescence in situ hybridization." Tanaka T., Inazawa J., Nakamura Y. Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Heart.
[2]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Skeletal muscle.
[5]	"Characterization of human cardiac calsequestrin and its deleterious mutants." Kim E., Youn B., Kemper L., Campbell C., Milting H., Varsanyi M., Kang C. J. Mol. Biol. 373:1047-1057(2007) [PubMed: 17881003] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.8 ANGSTROMS) OF 22-399, SUBUNIT, FUNCTION, CHARACTERIZATION OF VARIANTS CPVT2 GLN-33; HIS-167 AND HIS-307, CHARACTERIZATION OF VARIANTS ALA-66 AND MET-76.
[6]	"A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel." Lahat H., Pras E., Olender T., Avidan N., Ben-Asher E., Man O., Levy-Nissenbaum E., Khoury A., Lorber A., Goldman B., Lancet D., Eldar M. Am. J. Hum. Genet. 69:1378-1384(2001) [PubMed: 11704930] [Abstract] Cited for: VARIANT CPVT2 HIS-307.
[7]	"Molecular genetics of exercise-induced polymorphic ventricular tachycardia: identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms." Laitinen P.J., Swan H., Kontula K. Eur. J. Hum. Genet. 11:888-891(2003) [PubMed: 14571276] [Abstract] Cited for: VARIANTS ALA-66 AND MET-76.
[8]	"Calsequestrin mutant D307H exhibits depressed binding to its protein targets and a depressed response to calcium." Houle T.D., Ram M.L., Cala S.E. Cardiovasc. Res. 64:227-233(2004) [PubMed: 15485681] [Abstract] Cited for: CHARACTERIZATION OF VARIANT CPVT2 HIS-307.
[9]	"Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia." di Barletta M.R., Viatchenko-Karpinski S., Nori A., Memmi M., Terentyev D., Turcato F., Valle G., Rizzi N., Napolitano C., Gyorke S., Volpe P., Priori S.G. Circulation 114:1012-1019(2006) [PubMed: 16908766] [Abstract] Cited for: VARIANT CPVT2 HIS-167, CHARACTERIZATION OF VARIANT CPVT2 HIS-167.
[10]	"Catecholaminergic polymorphic ventricular tachycardia-related mutations R33Q and L167H alter calcium sensitivity of human cardiac calsequestrin." Valle G., Galla D., Nori A., Priori S.G., Gyorke S., de Filippis V., Volpe P. Biochem. J. 413:291-303(2008) [PubMed: 18399795] [Abstract] Cited for: VARIANTS CPVT2 GLN-33 AND HIS-167, CHARACTERIZATION OF VARIANTS CPVT2 GLN-33 AND HIS-167.
+	Additional computationally mapped references.

Web resources

GeneReviews

Wikipedia

Calsequestrin entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D55655 mRNA. Translation: BAA23494.1.
AL449264, AL450389 Genomic DNA. Translation: CAI14532.1.
AL450389, AL449264 Genomic DNA. Translation: CAI23373.1.
CH471122 Genomic DNA. Translation: EAW56635.1.
BC022288 mRNA. Translation: AAH22288.1.

IPI

IPI00298933.

RefSeq

NP_001223.2. NM_001232.3.

UniGene

Hs.57975.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2VAF	X-ray	3.80	A	22-399	[»]

ProteinModelPortal

O14958.

SMR

O14958. Positions 22-370.

ModBase

Search...

Protein-protein interaction databases

STRING

O14958.

PTM databases

PhosphoSite

O14958.

Proteomic databases

PRIDE

O14958.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000261448; ENSP00000261448; ENSG00000118729.

GeneID

845.

KEGG

hsa:845.

UCSC

uc001efx.2. human.

Organism-specific databases

CTD

845.

GeneCards

GC01M116242.

H-InvDB

HIX0000921.

HGNC

HGNC:1513. CASQ2.

HPA

HPA027285.

MIM

114251. gene.
611938. phenotype.

neXtProt

NX_O14958.

Orphanet

3286. Catecholinergic polymorphic ventricular tachycardia.

PharmGKB

PA26096.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG07435.

GeneTree

ENSGT00390000019377.

HOGENOM

HBG713932.

HOVERGEN

HBG050805.

InParanoid

O14958.

OMA

VYLLSSC.

OrthoDB

EOG4W0XD8.

PhylomeDB

O14958.

Gene expression databases

ArrayExpress

O14958.

Bgee

O14958.

CleanEx

HS_CASQ2.

Genevestigator

O14958.

GermOnline

ENSG00000118729. Homo sapiens.

Family and domain databases

InterPro

IPR001393. Calsequestrin.
IPR018233. Calsequestrin_CS.
IPR012336. Thioredoxin-like_fold.
[Graphical view]

Gene3D

G3DSA:3.40.30.10. Thioredoxin_fold. 3 hits.

PANTHER

PTHR10033. Calsequestrin. 1 hit.

Pfam

PF01216. Calsequestrin. 1 hit.
[Graphical view]

PRINTS

PR00312. CALSEQUESTRN.

SUPFAM

SSF52833. Thiordxn-like_fd. 3 hits.

PROSITE

PS00863. CALSEQUESTRIN_1. 1 hit.
PS00864. CALSEQUESTRIN_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

3542.

SOURCE

Search...

Entry information

Entry name

CASQ2_HUMAN

Accession

Primary (citable) accession number: O14958
Secondary accession number(s): Q5T1D2, Q8TBW8

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	September 19, 2002
Last modified:	January 25, 2012
This is version 105 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.