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FLASH GENE

Symbol

ATP2A1

contributors: mct - updated : 23-10-2017

HGNC name	ATPase, Ca++ transporting, cardiac muscle, fast twitch 1
HGNC id	811

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	BROD Brody myopathy
Location	16p11.2      Physical location : 28.889.808 - 28.915.830
Synonym name	skeletal muscle sarco(endo)-plasmic reticulum calcium ATPase
	calcium pump 1
	endoplasmic reticulum class 1/2 Ca
	sarcoplasmic reticulum Ca2+-ATPase
Synonym symbol(s)	ATP2A, SERCA1
EC.number	3.6.3.8

DNA

TYPE	functioning gene
STRUCTURE	26.02 kb     23 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site
text structure	MBNL1-binding sites in intron 22 (second and third MBNL1-binding motifs are necessary for MBNL1-dependent inclusion of exon 22 )

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	splicing regulation of ATP2A1 is well known to play important roles in muscle development and maturation

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004320 23 - 3570 NP_004311 109 994 adult fast- twitch muscle 2015 25487304 variant b or SERCA1 a longer transcript but shorter isoform adult form contains exon 22 has C-terminal glycine while SERCA1b has an octapeptide tail instead NM_173201 22 - 3528 NP_775293 110 1001 . neonatal fast twitch muscle . expressed in fetal/neonatal stages but is completely replaced by SERCA1a in adult muscle fiber 2015 25487304 SERCA1 b lacking an exon in the 3' coding region, resulting in a frameshift and use of a downstream termination codon compared to SERCA1 a SERCA1a has C-terminal glycine while SERCA1b has an octapeptide tail instead is associated with DM2 NM_001286075 21 splicing 3219 NP_001273004 - 859 - 2015 25487304 excluded exon 22, in skeletal muscle of DM1 patients sequestration of MBNL1 into the CUG repeat expansion of DMPK mRNA could cause the exclusion of ATP2A1 exon 22, and the expression of this aberrant splicing form could affect the regulation of Ca(2+) concentration of sarcoplasmic reticulum in DM1 patients S1T - - - - - localized in the ER-mitochondria microdomains 2015 25487304 truncated variant determines ER Ca(2+) depletion due to increased Ca(2+) leak, an increased number of ER-mitochondria contact sites, and inhibition of mitochondria movements by bridging ER stress to apoptosis through increased ER-mitochondria Ca(2+) transfer, S1T acts as an essential determinant of cellular fate

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth         Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   highly

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

neonatal

Text	transciently, in a minor form SERCA1B in neonatal fibers

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	ten transmembrane coiled coil helices (four of which containing Ca2+ binding sites)
	a cytoplasmic beta strand between TM2/3
	a phosphorylation and ATP binding globular domains, between TM4/5
	five YGCU(U/G)Y motifs that could potentially serve as MBNL1-binding motifs, in intron 22 (the second and third sites were important for regulation of exon 22 splicing)

HOMOLOGY

interspecies

ortholog to murine Atp2a1

Homologene

FAMILY	cation transport ATPase (P-type) family
	type IIA subfamily

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	sarco/endoplasmic reticulum

basic FUNCTION	intracellular pum catalyzing the hydrolysis of ATP couple with the translocation of Ca2+ from the cytosol to the sarcoplasmic reticulum lumen
	is essential for muscle function by transporting Ca(2+) from the cytosol into the sarcoplasmic reticulum through ATP hydrolysis
	in the cardiac muscle, SERCA hydrolyzes one ATP molecule to translocate two Ca(2+) ions into the SR membrane per enzymatic cycle
	PKC signaling is involved in the splicing of ATP2A1 and provide new evidence for a link between alternative splicing and PKC signaling
	re-sequestration of Ca(2+) into the sarcoplasmic reticulum is catalysed by ATP2A1, which has a key role in defining the contractile properties of skeletal and heart muscle tissue
	ATP2A1 function is controlled by PLN conformational equilibrium and phosphorylation promotes the B state via a conformational shift mechanism
	involved in muscular contraction and excitation
	its function depends on the equilibria between transient conformational states of PLN
	sarco(endo)plasmic reticulum Ca2+-ATPase of skeletal muscle, that is essential for muscle relaxation and maintenance of low resting Ca2+ levels in the myoplasm

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

ATP2A1/ PLN complex regulates Ca2+ translocation into the sarcoplasmic reticulum (SR) of cardiomyocytes and constitutes the main mechanism of cardiac relaxation (diastole)

INTERACTION

DNA

RNA

small molecule	metal binding, cofactor, nucleotide,
	ATP binding
	Ca2+ binding
	Mg2+ dependent

protein	associated with SLN and PLN
	unphosphorylated PLN reduces ATP2A1 affinity for Ca(2+) and affects the enzymatic turnover
	HSPA1A interacts with ATP2A1 to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with HSPA1A upregulation
	TRIM72 binds to sarcoplasmic reticulum Ca(2+)-ATPase 1a (ATP2A1) via its tripartite motif (TRIM) and PRY domains
	allosteric regulation of ATP2A1 depends on the conformational equilibrium of PLN
	EBF3 binds directly to the promoter of ATP2A1 and synergises with MYOD1 in the induction of ATP2A1
	SLN and PLN inhibit ATP2A1 by using a similar mechanism
	ANK1 interacts with ATP2A1 through its TM and cytoplasmic domains to regulate ATP2A1 activity and modulate sequestration of Ca(2+) in the sarcoplasmic reticulum lumen
	ANK1 interacts likely with SLN both directly and in complex with ATP2A1 and reduces SLN inhibitory effect on ATP2A1 activity
	role for TNFRSF11A as a key regulator of Ca(2+)storage and ATP2A1 activity, ultimately affecting denervated skeletal muscle function

cell & other

REGULATION

induced by

decreased contractile activity

inhibited by

PLN at low calcium concentration

repressed by

increased contractile activity

Other

sphingolipid could control the activity of the ATP2A1, and hence sphingosine may participate in the regulation of [Ca(2+)]I in mammalian cells

ASSOCIATED DISORDERS

corresponding disease(s)

BROD

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neuromuscular myopathy   novel therapeutic approach using ATP2A1 to abrogate the altered intracellular Ca(2+) levels that underlie most forms of Muscular dystrophies (MDs)

ANIMAL & CELL MODELS

	ATP2A1 null mice have progressive cyanosis and gasping respiration and succumb from respiratory failure shortly after birth
	a missense mutation in the ATP2A1 gene in congenital pseudomyotonia of Chianina cattle (the electromyographic examination does not show any alteration, not even during the phase of the muscle contraction) (Drögemüller 2008)