SLN

Summary

SLN (sarcolipin, HGNC:11089) is a protein-coding gene on chromosome 11q22.3, encoding Sarcolipin (O00631). Reversibly inhibits the activity of ATP2A1/SERCA1 and ATP2A2/SERCA2 in sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+).

Sarcoplasmic reticulum Ca(2+)-ATPases are transmembrane proteins that catalyze the ATP-dependent transport of Ca(2+) from the cytosol into the lumen of the sarcoplasmic reticulum in muscle cells. This gene encodes a small proteolipid that regulates several sarcoplasmic reticulum Ca(2+)-ATPases. The transmembrane protein interacts with Ca(2+)-ATPases and reduces the accumulation of Ca(2+) in the sarcoplasmic reticulum without affecting the rate of ATP hydrolysis.

Source: NCBI Gene 6588 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 6 total
• MANE Select transcript: NM_003063

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11089
Approved symbol	SLN
Name	sarcolipin
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC12301, MGC125854, MGC125855
Ensembl gene	ENSG00000170290
Ensembl biotype	protein_coding
OMIM	602203
Entrez	6588

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000305991, ENST00000525934, ENST00000531293, ENST00000960753, ENST00000960754, ENST00000960755, ENST00000960756

RefSeq mRNA: 1 — MANE Select: NM_003063 NM_003063

CCDS: CCDS31667

Canonical transcript exons

ENST00000305991 — 2 exons

Exon	Start	End
ENSE00001156474	107711963	107712056
ENSE00002197642	107707378	107708005

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 99.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.4306 / max 1157.8449, expressed in 163 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122127	3.0314	147
122128	0.3520	42
122126	0.0472	14

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	99.93	gold quality
triceps brachii	UBERON:0001509	99.92	gold quality
gluteal muscle	UBERON:0002000	99.92	gold quality
biceps brachii	UBERON:0001507	99.91	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.89	gold quality
skeletal muscle tissue	UBERON:0001134	99.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.86	gold quality
quadriceps femoris	UBERON:0001377	99.85	gold quality
vastus lateralis	UBERON:0001379	99.84	gold quality
body of tongue	UBERON:0011876	99.82	gold quality
deltoid	UBERON:0001476	99.79	gold quality
gastrocnemius	UBERON:0001388	99.77	gold quality
tibialis anterior	UBERON:0001385	99.69	gold quality
right atrium auricular region	UBERON:0006631	99.48	gold quality
muscle organ	UBERON:0001630	99.46	gold quality
cardiac atrium	UBERON:0002081	99.46	gold quality
skeletal muscle organ	UBERON:0014892	99.46	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.32	gold quality
muscle of leg	UBERON:0001383	99.30	gold quality
vena cava	UBERON:0004087	97.82	gold quality
muscle tissue	UBERON:0002385	96.81	gold quality
tongue	UBERON:0001723	94.02	gold quality
pharyngeal mucosa	UBERON:0000355	93.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.97	gold quality
saphenous vein	UBERON:0007318	88.80	gold quality
synovial joint	UBERON:0002217	88.52	gold quality
superior surface of tongue	UBERON:0007371	88.40	gold quality
apex of heart	UBERON:0002098	86.21	gold quality
tendon	UBERON:0000043	86.03	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting SLN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-657	99.48	66.02	848
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-4507	99.14	65.27	515
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-1237-3P	98.55	67.65	1423
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-4264	96.35	64.76	1480
HSA-MIR-1203	92.38	65.62	48

Literature-anchored findings (GeneRIF, showing 16)

• sarcolipin binds to phospholamban and inhibits polymerization (PMID:12032137)
• sarcolipin is likely to be an atrial chamber-specific regulator of Ca2+ cycling in heart (PMID:12645548)
• role in regulating sarco(endo)plasmic reticulum Ca2+-ATPase by binding to transmembrane helices alone or in association with phospholamban (PMID:12692302)
• Gene expression of SLN was studied in children with congenital heart defects. (PMID:17515962)
• The selective downregulation of SLN and enhanced sarcoplasmic reticulum Ca(2+) uptake in human AF suggest that SLN downregulation could play an important role in abnormal intracellular Ca(2+) cycling in atrial pathology. (PMID:21640081)
• The C-terminal tail of SLN is a distinct, essential domain in the regulation of SERCA. (PMID:23362265)
• SLN and PLN are co-expressed in most fibers, which suggests that super-inhibition of SERCAs may be physiologically important in the regulation of intracellular Ca2+ in human skeletal muscle. (PMID:24358354)
• Although SLN and PLB binding to SERCA have different functional outcomes on the coupling efficiency of SERCA, both proteins decrease the apparent Ca(2+) affinity of the pump, suggesting that SLN and PLB inhibit SERCA by using a similar mechanism. (PMID:25983321)
• Molecular dynamics simulations help to clarify and to understand better the SLN pentamer channel that had a hydrophobic gate and could switch Na(+) and Cl(-) ion permeability by hydrated and vacuum states. (PMID:26522287)
• Phospholamban and sarcolipin are membrane proteins that differentially regulate SERCA function. (Review) (PMID:26743715)
• analysis of transmembrane dynamics of the Thr-5 phosphorylated sarcolipin pentameric channel (PMID:27378083)
• Self-assembling study of sarcolipin and its mutants in multiple molecular dynamic simulations has been reported. (PMID:28241400)
• These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN’s inhibitory effect on SERCA1 activity. (PMID:28487373)
• Structure-Function Relationship of the SERCA Pump and Its Regulation by Phospholamban and Sarcolipin. (PMID:29594859)
• Sarcolipin protein is more abundantly expressed in leg than arm skeletal muscles in humans. Sarcolipin protein expression is not altered by short-term low-intensity exercise but is reduced by repeated sprint exercise. Expression in human skeletal muscle is not associated with adiposity nor resting energy expenditure in overweight men. (PMID:31674694)
• Effects of amino acid modifications on the permeability of the pentameric sarcolipin channel. (PMID:33244801)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Sarcolipin — O00631 (reviewed: O00631)

All UniProt accessions (2): O00631, A0A158RFT9

UniProt curated annotations — full annotation on UniProt →

Function. Reversibly inhibits the activity of ATP2A1/SERCA1 and ATP2A2/SERCA2 in sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). Also inhibits the activity of ATP2A3/SERCA3. Modulates calcium re-uptake during muscle relaxation and plays an important role in calcium homeostasis in muscle. Required for muscle-based, non-shivering thermogenesis.

Subunit / interactions. Homooligomer. Can also form heterooligomers with other sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) regulators ARLN, ERLN, PLN and STRIT1/DWORF. Monomer. Interacts with calcium ATPase ATP2A1/SERCA1. Interacts as a monomer with ATP2A2/SERCA2; the interaction decreases ATP2A2 Ca(2+) affinity. Interacts with VMP1; VMP1 competes with PLN and SLN to prevent them from forming an inhibitory complex with ATP2A2.

Subcellular location. Sarcoplasmic reticulum membrane. Endoplasmic reticulum membrane.

Similarity. Belongs to the sarcolipin family.

RefSeq proteins (1): NP_003054* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008028	Sarcolipin	Family

Pfam: PF05366

UniProt features (6 total): topological domain 2, peptide 1, transmembrane region 1, strand 1, helix 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1JDM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00631-F1	91.70	0.78

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-5578775	Ion homeostasis
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction
R-HSA-983712	Ion channel transport

MSigDB gene sets: 158 (showing top): GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, chr11q22, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_NEGATIVE_REGULATION_OF_ATP_DEPENDENT_ACTIVITY, TAL1ALPHAE47_01, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_DISASSEMBLY, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, NKX62_Q2, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_CALCIUM_ION_IMPORT, GOBP_NEGATIVE_REGULATION_OF_CALCIUM_ION_IMPORT, GOBP_REGULATION_OF_CALCIUM_ION_IMPORT

GO Biological Process (11): calcium ion transport (GO:0006816), negative regulation of protein-containing complex disassembly (GO:0043242), regulation of calcium ion transport (GO:0051924), sarcoplasmic reticulum calcium ion transport (GO:0070296), negative regulation of calcium ion import (GO:0090281), positive regulation of cold-induced thermogenesis (GO:0120162), regulation of relaxation of muscle (GO:1901077), positive regulation of protein depolymerization (GO:1901881), regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901894), negative regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901895), negative regulation of calcium ion import into sarcoplasmic reticulum (GO:1902081)

GO Molecular Function (4): enzyme inhibitor activity (GO:0004857), ATPase binding (GO:0051117), protein binding (GO:0005515), enzyme regulator activity (GO:0030234)

GO Cellular Component (5): membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), sarcoplasmic reticulum membrane (GO:0033017), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cardiac conduction	1
Ion channel transport	1
Muscle contraction	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion transport	2
negative regulation of calcium ion transport	2
P-type calcium transporter activity	2
catalytic activity	2
metal ion transport	1
protein-containing complex disassembly	1
regulation of protein-containing complex disassembly	1
negative regulation of cellular component organization	1
regulation of metal ion transport	1
calcium ion import	1
regulation of calcium ion import	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
relaxation of muscle	1
regulation of muscle system process	1
positive regulation of protein-containing complex disassembly	1
protein depolymerization	1
regulation of protein depolymerization	1
regulation of transmembrane transporter activity	1
regulation of ATP-dependent activity	1
negative regulation of ATP-dependent activity	1
negative regulation of calcium ion transmembrane transporter activity	1
regulation of ATPase-coupled calcium transmembrane transporter activity	1
negative regulation of intracellular transport	1
regulation of calcium ion import into sarcoplasmic reticulum	1
calcium ion import into sarcoplasmic reticulum	1
enzyme regulator activity	1
molecular function inhibitor activity	1
enzyme binding	1
binding	1
molecular function regulator activity	1
cellular anatomical structure	1
endoplasmic reticulum	1
sarcoplasm	1
endoplasmic reticulum membrane	1
sarcoplasmic reticulum	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLN	ATP2A1	O14983	991
SLN	PLN	P26678	970
SLN	ATP2A2	P16614	879
SLN	ATP2A3	Q93084	857
SLN	STRIT1	P0DN84	848
SLN	TRAM2	Q15035	764
SLN	MRLN	P0DMT0	756
SLN	ERLN	P0DI80	606
SLN	ARLN	Q8WVX3	587
SLN	RYR1	P21817	567
SLN	SLC8A1	P32418	555
SLN	CASQ1	P31415	545
SLN	UCP1	P25874	540
SLN	RYR2	Q92736	537
SLN	ATP2B1	P20020	523

IntAct

13 interactions, top by confidence:

A	B	Type	Score
SLN	TMEM79	psi-mi:“MI:0915”(physical association)	0.670
SLN	SYNE4	psi-mi:“MI:0915”(physical association)	0.560
KASH5	SLN	psi-mi:“MI:0915”(physical association)	0.560
SYNE4	SLN	psi-mi:“MI:0915”(physical association)	0.560
SLN	SERCA	psi-mi:“MI:0915”(physical association)	0.400
SLN	PTPN11	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (13): TMEM79 (Two-hybrid), CCDC155 (Two-hybrid), SYNE4 (Two-hybrid), SLN (Two-hybrid), SLN (Two-hybrid), ATP2A1 (Affinity Capture-Western), PLN (Affinity Capture-Western), ATP2A1 (Affinity Capture-Western), ATP2A2 (Affinity Capture-Western), PLN (Affinity Capture-Western), SLN (Affinity Capture-Western), SLN (Affinity Capture-Western), VMP1 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GWH6, A0A7H0DN68, A0A7H0DNB3, A0T0B1, A0T0B4, A0T0P6, A2BVK2, A4ZUB9, A4ZUC7, A5A617, B7K767, C0HJH3, C0HJH4, C7J0R5, O00631, O78448, P0C2G8, P0CAJ2, P0CAJ3, P0CAJ4, P0CK21, P0CK22, P0DN84, P0DPN0, P0DPO4, P0DPO8, P0DTF1, P0DTI0, P11339, P15911, P30396, P37256, P48109, P49487, P49516, P64442, P64443, P64444, P9WEJ6, Q06J23

Diamond homologs: O00631, P42532, Q6SLE7, Q9CQD6

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
SLN	“down-regulates activity”	ATP2A1	binding
ANK1	“down-regulates activity”	SLN	binding
CAMK2A	“down-regulates activity”	SLN	phosphorylation
SLN	“down-regulates activity”	ATP2A2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

6 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	6
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

413 predictions. Top by Δscore:

Variant	Effect	Δscore
11:107708016:A:C	acceptor_gain	0.9900
11:107716119:TATC:T	donor_gain	0.9900
11:107716120:ATCA:A	donor_gain	0.9900
11:107719611:CTTA:C	donor_loss	0.9900
11:107719612:TTAC:T	donor_loss	0.9900
11:107719613:TAC:T	donor_loss	0.9900
11:107719614:ACCT:A	donor_loss	0.9900
11:107719614:ACCTG:A	donor_gain	0.9900
11:107719615:CCTGC:C	donor_gain	0.9900
11:107708004:TCCTG:T	acceptor_gain	0.9800
11:107708015:C:CT	acceptor_gain	0.9800
11:107719615:CCTG:C	donor_gain	0.9800
11:107719614:A:AC	donor_gain	0.9700
11:107719615:C:CC	donor_gain	0.9700
11:107708002:CCTC:C	acceptor_gain	0.9600
11:107708003:CTCC:C	acceptor_gain	0.9600
11:107719498:C:CA	donor_gain	0.9600
11:107719618:G:A	donor_gain	0.9500
11:107718289:A:AG	acceptor_gain	0.9400
11:107719610:ACTT:A	donor_loss	0.9400
11:107708003:CTC:C	acceptor_gain	0.9200
11:107712684:G:GT	donor_gain	0.9200
11:107708009:A:C	acceptor_gain	0.9100
11:107718024:C:CT	donor_gain	0.9100
11:107718025:T:TT	donor_gain	0.9100
11:107718289:AACT:A	acceptor_gain	0.9100
11:107708005:CCTGA:C	acceptor_gain	0.9000
11:107708003:CTCCT:C	acceptor_loss	0.8900
11:107708004:TCC:T	acceptor_loss	0.8900
11:107715101:G:C	donor_gain	0.8900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000037969 (11:107709604 T>A,G), RS1000411841 (11:107709913 T>C), RS1000818378 (11:107709838 C>G,T), RS1001147919 (11:107711708 T>C), RS1001456574 (11:107711323 A>G,T), RS1001855909 (11:107709030 A>C,G), RS1002457015 (11:107710372 T>C), RS1002533531 (11:107713362 T>C), RS1002621541 (11:107710805 T>A,C,G), RS1002885517 (11:107707656 T>A,C), RS1003116410 (11:107707297 C>G,T), RS1003951966 (11:107709040 C>T), RS1004004399 (11:107707195 C>G,T), RS1004723769 (11:107710589 G>T), RS1005007784 (11:107708879 T>C)

Disease associations

OMIM: gene MIM:602203 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment	3
methylmercuric chloride	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases abundance, decreases expression	1
Cisplatin	decreases expression	1
Cytarabine	decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Lead	affects expression	1
Silicon Dioxide	decreases expression	1
Tamoxifen	decreases expression, affects cotreatment	1
Thiram	increases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Aflatoxin B1	decreases methylation	1
Medroxyprogesterone Acetate	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	increases expression	1
Raloxifene Hydrochloride	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.