Tbio AGRN Agrin

Protein Summary

Description

Isoform 1: heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain. Isoform 2: transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases. Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms. Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation. Agrin N-terminal 110 kDa subunit: is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity). Agrin C-terminal 22 kDa fragment: this released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia. This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

Uniprot Accession IDs

• O00468
• Q5SVA1
• Q5SVA2
• Q60FE1
• Q7KYS8
• Q8N4J5
• Q96IC1
• Q9BTD4

Gene Name

• AGRN

Ensembl ID

• ENST00000379370
• ENSP00000368678
• ENSG00000188157

Symbol

• AGRIN
• CMS8
• AGRIN
• CMSPPD

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
protein domain	1
biological process	0.95
molecular function	0.88
virus perturbation	0.88
disease perturbation	0.87

Protein Classes

PANTHER Classes

Protein / Receptor / Agrin

Protein / Extracellular Matrix Protein / Extracellular Matrix Linker Protein / Agrin

Protein / ... / Protease Inhibitor / Agrin

DTO Classes

Protein / Enzyme Modulator / Protease Inhibitor / Agrin

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 731.4   (req: < 5)

Gene RIFs: 29   (req: <= 3)

Antibodies: 199   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 731.4   (req: >= 5)

Gene RIFs: 29   (req: > 3)

Antibodies: 199   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 21

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 0

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

Expression Data (0 Tissues)

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No expression data found

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Related Tools (4)

Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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Approved Drugs (0)

No approved drugs found

Active Ligands (0)

No active ligands found

Protein-Protein Interactions (199)

Explore Interacting Targets

1 – 10 of 199

• See Interactions on String-DB

CAMKV

Tbio

Family:  Kinase

Novelty:  0.17794181

p_int:  0.999985397

p_ni:  0.000014596

p_wrong:  8e-9

Score:  0.202

Data Source:  BioPlex,STRINGDB

HADHA

Tbio

Novelty:  0.00385746

p_int:  0.999979003

p_ni:  0.000020985

p_wrong:  1.2e-8

Data Source:  BioPlex

CRP

Tbio

Novelty:  0.00001517

p_int:  0.999966555

p_ni:  0.000033443

p_wrong:  2e-9

Score:  0.219

Data Source:  BioPlex,STRINGDB

OS9

Tbio

Novelty:  0.01490339

p_int:  0.999626037

p_ni:  0.00035002

p_wrong:  0.000023943

Data Source:  BioPlex

MAX

Tbio

Family:  TF

Novelty:  0.00799068

p_int:  0.996951098

p_ni:  0.002882733

p_wrong:  0.000166168

Data Source:  BioPlex

CCL3L1

Tbio

Novelty:  0.01124082

p_int:  0.991257591

p_ni:  0.008725881

p_wrong:  0.000016528

Data Source:  BioPlex

ZFP41

Tdark

Family:  TF

Novelty:  3.33093006

p_int:  0.852737425

p_ni:  0.000225314

p_wrong:  0.147037261

Data Source:  BioPlex

OLFM3

Tbio

Novelty:  0.10234408

p_int:  0.847916659

p_ni:  0.000771509

p_wrong:  0.151311832

Score:  0.282

Data Source:  BioPlex,STRINGDB

MUSK

Tchem

Family:  Kinase

Novelty:  0.00151518

Score:  0.997

Data Source:  Reactome,STRINGDB

DAG1

Tbio

Family:  Enzyme

Novelty:  0.00149278

Score:  0.996

Data Source:  Reactome,STRINGDB

Nearest Tclin Targets

Nearest Tclin calculations are only available for targets with KEGG Pathway annotations.

Pathways (88)

Reactome (32)

KEGG (1)

PathwayCommons (8)

WikiPathways (47)

A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)

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1 – 5 of 32

Data Source	Name	Explore in Pharos	Explore in Source
Reactome	A tetrasaccharide linker sequence is required for GAG synthesis	26 targets	R-HSA-1971475
Reactome	Axon guidance	533 targets	R-HSA-422475
Reactome	Chondroitin sulfate/dermatan sulfate metabolism	50 targets	R-HSA-1793185
Reactome	Defective B3GALT6 causes EDSP2 and SEMDJL1	20 targets	R-HSA-4420332
Reactome	Defective B3GAT3 causes JDSSDHD	20 targets	R-HSA-3560801

Name	Explore in Pharos	Explore in Source
A tetrasaccharide linker sequence is required for GAG synthesis	26 targets	R-HSA-1971475
Axon guidance	533 targets	R-HSA-422475
Chondroitin sulfate/dermatan sulfate metabolism	50 targets	R-HSA-1793185
Defective B3GALT6 causes EDSP2 and SEMDJL1	20 targets	R-HSA-4420332
Defective B3GAT3 causes JDSSDHD	20 targets	R-HSA-3560801

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (32)

Functions (8)

Components (11)

Processes (13)

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10

1 – 8 of 8

GO Term	Evidence	Assigned by
extracellular matrix structural constituent	Inferred from High Throughput Direct Assay (HDA)	BHF-UCL
calcium ion binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
chondroitin sulfate binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
dystroglycan binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
heparan sulfate proteoglycan binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
sialic acid binding	Inferred from Sequence or structural Similarity (ISS)	UniProtKB
laminin binding	Traceable Author Statement (TAS)	UniProtKB
structural constituent of cytoskeleton	Traceable Author Statement (TAS)	UniProtKB

Disease Associations (null)

No disease associations found

GWAS Traits (14)

• Explore on Target Illumination GWAS Analytics (TIGA)

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1 – 5 of 14

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
pancreatic carcinoma	EFO_0002618	1	1	0	1.3	78.8
blood protein measurement	EFO_0007937	1	2	2		66
educational attainment	EFO_0011015	1	2	2		64.5
brain measurement	EFO_0004464	1	1	0	6.9	42.6
high density lipoprotein cholesterol measurement	EFO_0004612	3	2	3		41.8

• Explore on Target Illumination GWAS Analytics (TIGA)

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5

1 – 5 of 14

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
pancreatic carcinoma	EFO_0002618	0	1.3	78.8
blood protein measurement	EFO_0007937	2		66
educational attainment	EFO_0011015	2		64.5
brain measurement	EFO_0004464	0	6.9	42.6
high density lipoprotein cholesterol measurement	EFO_0004612	3		41.8

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UniProt Keyword Find Similar Targets

No Header	No Header
Alternative splicing
Calcium
Cell junction
Cell membrane
Complete proteome
Congenital myasthenic syndrome
Developmental protein
Differentiation
Disease mutation
Disulfide bond

GWAS Trait Find Similar Targets

No Header	No Header
alkaline phosphatase measurement
apolipoprotein A 1 measurement
blood protein measurement
brain measurement
calcium measurement
cortical surface area measurement
educational attainment
heel bone mineral density
high density lipoprotein cholesterol measurement
hip bone size

MGI Phenotype Find Similar Targets

No Header	No Header
behavior/neurological phenotype
cardiovascular system phenotype
growth/size/body region phenotype
limbs/digits/tail phenotype
mortality/aging
muscle phenotype
nervous system phenotype
renal/urinary system phenotype
respiratory system phenotype

IDG Resources

No IDG generated resources found

Orthologs (11)

1 – 5 of 11

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	agrin	VGNC:48969	100609326
Macaque	agrin		700400
Mouse	agrin	MGI:87961	11603
Rat	agrin	RGD:2067	25592
Dog	agrin	VGNC:37716	479574

Species	Name	OMA	EggNOG	Inparanoid
Chimp	agrin
Macaque	agrin
Mouse	agrin
Rat	agrin
Dog	agrin

Publication Statistics

PubMed Score 731.40

PubMed score by year

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PubTator Score 375.31

PubTator score by year

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Related Publications

Text Mined References (55)

GeneRif Annotations (29)

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PMID	Year	Title