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Category Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21

GIFtS
-

AGRN Gene

protein-coding GIFtS: 65
GCID: GC01P000946

agrin

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(According to ¹HGNC, ²Entrez Gene,
³UniProtKB/Swiss-Prot, ⁴UniProtKB/TrEMBL, ⁵OMIM, ⁶GeneLoc, ⁷Ensembl, ⁸DME, ⁹miRBase, and/or ¹⁰fRNAdb)
About This Section

Aliases
Agrin¹
AGRIN¹ ³
Agrin Proteoglycan²

External Ids:	HGNC: 329¹	Entrez Gene: 375790²	Ensembl: ENSG00000188157⁷	OMIM: 103320⁵	UniProtKB: O00468³

Export aliases for AGRN gene to outside databases

Previous GC identifers: GC01P000484 GC01P000708 GC01U900219 GC00P9W0144 GC01P000996 GC01P000226

(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for AGRN:

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. (provided by RefSeq, Aug 2011)

UniProtKB/Swiss-Prot: AGRIN_HUMAN, O00468

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

Function: 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

Function: 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

Function: Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell

differentiation

Function: 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)

Function: 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

Gene Wiki entry for AGRN (Agrin)

(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section

RefSeq DNA sequence:

NC_000001.10 NC_018912.1 NT_004350.19

Regulatory elements:

SABiosciences Regulatory transcription factor binding sites in the AGRN gene promoter:
CREB p53 deltaCREB MyoD STAT3
Other transcription factors

SwitchGear Promoter luciferase reporter plasmid: AGRN promoter sequence

Search SABiosciences Chromatin IP Primers for AGRN

Epigenetics:

QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat AGRN

Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 1p36.33 Ensembl cytogenetic band: 1p36.33 HGNC cytogenetic band: 1p36.33

AGRN Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
AGRN gene location

GeneLoc information about chromosome 1 GeneLoc Exon Structure

GeneLoc location for GC01P000946: view genomic region (about GC identifiers)

Start:	955,503 bp from pter	End:	991,496 bp from pter
Size:	35,994 bases	Orientation:	plus strand

(According to ¹UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to ²PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
About This Section

UniProtKB/Swiss-Prot: AGRIN_HUMAN, O00468 (See protein sequence)

Recommended Name: Agrin precursor

Size: 2067 amino acids; 217232 Da

Subunit: Monomer (By similarity). Interacts (N-terminal subunit) with TGF-beta family members, BMP2 AND BMP4; the

interactions inhibit the activity of these growth factors. Interacts with TGFB1; the interaction enhances the activity

of TGFB1 (By similarity). Component of the AGRN-LRP4 complex that consists of a tetramer of two AGRN-LRP4

heterodimers. Interacts (via the laminin G-like 3 domain) directly with LRP4; the interaction is required for

activation of MUSK and clustering of AChR and requires the 'z8' insert present in the z(+8) isoforms. Interacts with

DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN

Subcellular location: Isoform 1: Secreted, extracellular space, extracellular matrix. Note=Synaptic basal lamina at the

neuromuscular junction (By similarity)

Subcellular location: Isoform 2: Cell junction, synapse. Cell membrane; Single-pass type II membrane protein

Miscellaneous: Cleaved C-terminal fragments may be used as a biomarker for sarcopenia, age-related progressive loss of

skeletal muscle (PubMed:22683512)

Caution: The unknown residue 'x' in the transmembrane isoform is probably a proline residue by similarity to mouse and

rat sequences

Secondary accessions: Q5SVA1 Q5SVA2 Q60FE1 Q7KYS8 Q8N4J5 Q96IC1 Q9BTD4

Alternative splicing: 7 isoforms: O00468-1 O00468-2 O00468-3 O00468-4 O00468-5 O00468-6 O00468-7 (Produced by usage of an alternative first exon)

Explore the universe of human proteins at neXtProt for AGRN: NX_O00468

Post-translational modifications:

Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked

oligosaccharides. Glycosaminoglycans (GAGs), present in the N-terminal 110 kDa fragment, are required for induction of

filopodia in hippocampal neurons. The first cluster (Gly/Ser-rich) for GAG attachment contains heparan sulfate (HS)

chains and the second cluster (Ser/Thr-rich), contains chondroitin sulfate (CS) chains. Heparin and heparin sulfate

binding in the G3 domain is independent of calcium ions. Binds heparin with a stoichiometry of 2:1. Binds sialic acid

with a stoichiometry of 1:1 and binding requires calcium ions (By similarity)¹

At synaptic junctions, cleaved at two conserved sites, alpha and beta, by neurotrypsin. Cleavage at the alpha-site

produces the agrin N-terminal 110-kDa subunit and the agrin C-terminal 110-kDa subunit. Further cleavage of agrin

C-terminal 110-kDa subunit at the beta site produces the C-terminal fragments, agrin C-terminal 90 kDa fragment and

agrin C-terminal 22 kDa fragment. Excessive cleavage at the beta-site releases large amounts of the agrin C-terminal

22 kDa fragment leading to destabilization at the neuromuscular junction (NMJ)¹

View modification sites using PhosphoSitePlus²

View neXtProt modification sites for NX_O00468

AGRN Protein expression data from MOPED and PaxDb: About this image

REFSEQ proteins: NP_940978.2

ENSEMBL proteins:

ENSP00000368678 ENSP00000400771

Reactome Protein details: O00468
Human Recombinant Protein Products:

	Browse Purified and Recombinant Proteins at EMD Millipore
	R&D Systems Recombinant & Natural Proteins for AGRN (Agrin)
	Browse recombinant and purified proteins available from Enzo Life Sciences
	Browse OriGene full length recombinant human proteins expressed in human HEK293 cells Browse OriGene Protein Over-expression Lysates OriGene Custom Protein Services for AGRN
	GenScript Custom Purified and Recombinant Proteins Services for AGRN
	Browse Sino Biological Recombinant Proteins
	Browse ProSpec Recombinant Proteins
	Uscn Proteins for AGRN

Gene Ontology (GO): 5/11 cellular component terms (GO ID links to tree view) (see all 11): About this table

GO ID	Qualified GO term	Evidence	PubMed IDs
GO:0005604	basement membrane	--	--
GO:0005605	basal lamina	IDA	9405491
GO:0005615	extracellular space	--	--
GO:0005796	Golgi lumen	TAS	--
GO:0005886	plasma membrane	TAS	--

AGRN for ontologies About GeneDecksing

AGRN Antibody Products:

	EMD Millipore Mono- and Polyclonal Antibodies for the study of AGRN
	R&D Systems Antibodies for AGRN (Agrin)
	Browse OriGene Antibodies OriGene Custom Antibody Services for AGRN
	GenScript Custom Superior Antibodies Services for AGRN
	Novus Biologicals AGRN Antibodies
	Search for Antibodies for AGRN at Abcam
	Uscn Antibodies for AGRN
	Search ThermoFisher Antibodies for AGRN

Assay Products for AGRN:

	Browse Kits and Assays available from EMD Millipore
	OriGene Custom Immunoassay Development Browse OriGene Fluorogenic Cell Assay Kits
	Browse R&D Systems for biochemical assays
	GenScript Custom Assay Services for AGRN
	Browse Enzo Life Sciences for kits & assays
	Uscn ELISAs and CLIAs for AGRN

(According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
About This Section

AGRN for domains About GeneDecksing

5/12 InterPro domains/families (see all 12):

IPR008993 TIMP-like_OB-fold

IPR002350 Prot_inh_Kazal

IPR000082 SEA

IPR000742 EG-like_dom

IPR013320 ConA-like_subgrp

Graphical View of Domain Structure for InterPro Entry O00468

ProtoNet protein and cluster: O00468

5/7 Blocks protein families (see all 7):

IPB000082 SEA domain

IPB001455 Protein of unknown function UPF0033

IPB001791 Laminin G

IPB001881 EGF-like calcium-binding

IPB006210 Type I EGF

UniProtKB/Swiss-Prot: AGRIN_HUMAN, O00468

Domain: The NtA domain, absent in TM-agrin, is required for binding laminin and connecting to basal lamina

Domain: Both laminin G-like 2 (G2) and laminin G-like 3 (G3) domains are required for alpha-dystroglycan/DAG1 binding.

G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding (By similarity)

Similarity: Contains 4 EGF-like domains

Similarity: Contains 9 Kazal-like domains

Similarity: Contains 2 laminin EGF-like domains

Similarity: Contains 3 laminin G-like domains

Similarity: Contains 1 NtA (N-terminal agrin) domain

Similarity: Contains 1 SEA domain

(According to ¹UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or ²DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013,
bound targets from SABiosciences, miRNA Gene Targets from miRTarBase shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
About This Section

Function Summary: