InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: AGRN

Summary

InnateDB Protein

IDBP-84352.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

AGRN

Protein Name

agrin

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000368678

InnateDB Gene

IDBG-84350 (AGRN)

Protein Structure

UniProt Annotation

Function

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 homestasis 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). {ECO:0000250}.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.

Subcellular Localization

Isoform 1: Secreted, extracellular space, extracellular matrix. Note=Synaptic basal lamina at the neuromuscular junction. {ECO:0000250}.Isoform 2: Cell junction, synapse. Cell membrane; Single-pass type II membrane protein.

Disease Associations

Myasthenia, limb-girdle, familial (LGM) [MIM:254300]: A congenital myasthenic syndrome characterized by a typical 'limb girdle' pattern of muscle weakness with small, simplified neuromuscular junctions but normal acetylcholine receptor and acetylcholinesterase function. {ECO:0000269PubMed:19631309, ECO:0000269PubMed:22205389}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in basement membranes of lung and kidney. Muscle- and neuron-specific isoforms are found. Isoforms (y+) with the 4 AA insert and (z+8) isoforms with the 8 AA insert are all neuron-specific. Isoforms (z+11) are found in both neuronal and non-neuronal tissues. {ECO:0000269PubMed:16487930, ECO:0000269PubMed:20551380, ECO:0000269PubMed:9652404}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 11 experimentally validated interaction(s) in this database.
They are also associated with 4 interaction(s) predicted by orthology.

Experimentally validated
Total	11 [view]
Protein-Protein	11 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	4 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0002162	dystroglycan binding
GO:0005200	structural constituent of cytoskeleton
GO:0005509	calcium ion binding
GO:0005515	protein binding
GO:0030548	acetylcholine receptor regulator activity
GO:0033691	sialic acid binding
GO:0035374	chondroitin sulfate binding
GO:0043236	laminin binding
GO:0043395	heparan sulfate proteoglycan binding

Biological Process

GO:0001523	retinoid metabolic process
GO:0005975	carbohydrate metabolic process
GO:0006024	glycosaminoglycan biosynthetic process
GO:0006027	glycosaminoglycan catabolic process
GO:0007009	plasma membrane organization
GO:0007165	signal transduction
GO:0007213	G-protein coupled acetylcholine receptor signaling pathway
GO:0007268	synaptic transmission
GO:0007411	axon guidance
GO:0007528	neuromuscular junction development
GO:0007603	phototransduction, visible light
GO:0008582	regulation of synaptic growth at neuromuscular junction
GO:0010469	regulation of receptor activity
GO:0030198	extracellular matrix organization
GO:0030203	glycosaminoglycan metabolic process
GO:0030204	chondroitin sulfate metabolic process
GO:0032321	positive regulation of Rho GTPase activity
GO:0043113	receptor clustering
GO:0043525	positive regulation of neuron apoptotic process
GO:0044281	small molecule metabolic process
GO:0045162	clustering of voltage-gated sodium channels
GO:0045213	neurotransmitter receptor metabolic process
GO:0045887	positive regulation of synaptic growth at neuromuscular junction
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0050808	synapse organization
GO:0051491	positive regulation of filopodium assembly

Cellular Component

GO:0005576	extracellular region
GO:0005604	basement membrane
GO:0005605	basal lamina
GO:0005615	extracellular space
GO:0005737	cytoplasm
GO:0005796	Golgi lumen
GO:0005886	plasma membrane
GO:0009986	cell surface
GO:0016021	integral component of membrane
GO:0030054	cell junction
GO:0031012	extracellular matrix
GO:0043202	lysosomal lumen
GO:0045202	synapse
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

InterPro

IPR000082 SEA domain
IPR000742 Epidermal growth factor-like domain
IPR001791 Laminin G domain
IPR001881 EGF-like calcium-binding domain
IPR002049 EGF-like, laminin
IPR002350 Kazal domain
IPR003645 Follistatin-like, N-terminal
IPR003884 Factor I / membrane attack complex
IPR004850 Agrin NtA domain
IPR008985 Concanavalin A-like lectin/glucanases superfamily
IPR008993 Tissue inhibitor of metalloproteinases-like, OB-fold

PFAM