UniProt functional annotation for P31696



	UniProt functional annotation for P31696

UniProt code: P31696.

Organism: Gallus gallus (Chicken).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda; Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae; Phasianinae; Gallus.

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 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.

Function: [Isoform 9]: transmembrane agrin (TM-agrin), the predominant 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 2, isoform 4 and isoform 7: muscle agrin isoforms, which lack the 8-amino acid insert at the 'B' site, but with the insert at the'A' site have no AChr clustering activity nor MUSK activation but bind heparin. Bind alpha-dystroglycan with lower affinity.

Function: [Isoform 5]: muscle agrin A0B0 lacking inserts at both 'A' and 'B' sites has no heparin-binding nor AChR clustering activity but binds strongly alpha-dystroglycan.

Function: [Agrin N-terminal 110 kDa subunit]: is involved in modulation of growth factor signaling (By similarity). Involved also in the 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. {ECO:0000250, ECO:0000269|PubMed:11425874, ECO:0000269|PubMed:15198666, ECO:0000269|PubMed:17012237, ECO:0000269|PubMed:17649979, ECO:0000269|PubMed:19940118, ECO:0000269|PubMed:22984437, ECO:0000269|PubMed:7860635}.

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 'B' splice variants of this fragment also show an increase in the number of filopodia.

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. 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 'B8' insert present in the B8 isoforms. Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN. {ECO:0000250, ECO:0000269|PubMed:11473262, ECO:0000269|PubMed:15016366, ECO:0000269|PubMed:15694127, ECO:0000269|PubMed:17012237, ECO:0000269|PubMed:17649979, ECO:0000269|PubMed:8522611, ECO:0000269|PubMed:8607994}.

Subcellular location: [Isoform 1]: Secreted, extracellular space, extracellular matrix {ECO:0000269|PubMed:11161480, ECO:0000269|PubMed:8522611}. Note=Synaptic basal lamina at the neuromuscular junction. {ECO:0000269|PubMed:11161480}.

Subcellular location: [Isoform 9]: Cell junction, synapse {ECO:0000269|PubMed:11161480}. Cell membrane {ECO:0000269|PubMed:11161480}; Single-pass type II membrane protein {ECO:0000269|PubMed:11161480}.

Tissue specificity: Detected in embryonic brain, spinal cord, skeletal muscle, vitreous humor and liver (at protein level). {ECO:0000269|PubMed:8522611}.

Domain: The 4 amino acid insert at the 'A' site is required for efficient binding of heparin.

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 binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding.

Ptm: 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 (By similarity). C-terminal heparin and heparin sulfate binding 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. Inserts at the 'B' site have no effect on sialic acid binding. {ECO:0000250, ECO:0000269|PubMed:8522611}.

Ptm: At synaptic junctions, cleaved at two conserved sites, alpha and beta, by neurotrypsin. Cleavage at the alpha-site produces the N- and C- terminal 110-kDa subunits. Further cleavage of the C-terminal at the beta site produces C-terminal fragments, C22 and C90, of 90 kDa and 22 kDa respectively (By similarity). {ECO:0000250}.

Ptm: Proteolytically cleaved in vitro in both the N-terminal and C- terminal by several matrix metaloproteinases (MMPs). {ECO:0000269|PubMed:22984437}.

Miscellaneous: [Isoform 9]: Transmembrane isoform produced by usage of an alternative first exon. {ECO:0000305}.

Sequence caution: Sequence=AAA48585.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Gallus gallus (Chicken).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Archelosauria; Archosauria; Dinosauria; Saurischia; Theropoda; Coelurosauria; Aves; Neognathae; Galloanserae; Galliformes; Phasianidae; Phasianinae; Gallus.



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 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.



Function:		[Isoform 9]: transmembrane agrin (TM-agrin), the predominant 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 2, isoform 4 and isoform 7: muscle agrin isoforms, which lack the 8-amino acid insert at the 'B' site, but with the insert at the'A' site have no AChr clustering activity nor MUSK activation but bind heparin. Bind alpha-dystroglycan with lower affinity.



Function:		[Isoform 5]: muscle agrin A0B0 lacking inserts at both 'A' and 'B' sites has no heparin-binding nor AChR clustering activity but binds strongly alpha-dystroglycan.



Function:		[Agrin N-terminal 110 kDa subunit]: is involved in modulation of growth factor signaling (By similarity). Involved also in the 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. {ECO:0000250, ECO:0000269\|PubMed:11425874, ECO:0000269\|PubMed:15198666, ECO:0000269\|PubMed:17012237, ECO:0000269\|PubMed:17649979, ECO:0000269\|PubMed:19940118, ECO:0000269\|PubMed:22984437, ECO:0000269\|PubMed:7860635}.



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 'B' splice variants of this fragment also show an increase in the number of filopodia.


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. 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 'B8' insert present in the B8 isoforms. Interacts with DAG1; the interaction is influenced by cell surface glycosaminoglycans and by alternative splicing of AGRN. {ECO:0000250, ECO:0000269\|PubMed:11473262, ECO:0000269\|PubMed:15016366, ECO:0000269\|PubMed:15694127, ECO:0000269\|PubMed:17012237, ECO:0000269\|PubMed:17649979, ECO:0000269\|PubMed:8522611, ECO:0000269\|PubMed:8607994}.
Subcellular location:		[Isoform 1]: Secreted, extracellular space, extracellular matrix {ECO:0000269\|PubMed:11161480, ECO:0000269\|PubMed:8522611}. Note=Synaptic basal lamina at the neuromuscular junction. {ECO:0000269\|PubMed:11161480}.
Subcellular location:		[Isoform 9]: Cell junction, synapse {ECO:0000269\|PubMed:11161480}. Cell membrane {ECO:0000269\|PubMed:11161480}; Single-pass type II membrane protein {ECO:0000269\|PubMed:11161480}.
Tissue specificity:		Detected in embryonic brain, spinal cord, skeletal muscle, vitreous humor and liver (at protein level). {ECO:0000269\|PubMed:8522611}.
Domain:		The 4 amino acid insert at the 'A' site is required for efficient binding of heparin.
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 binding. G3 domain is required for C-terminal heparin, heparan sulfate and sialic acid binding.
Ptm:		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 (By similarity). C-terminal heparin and heparin sulfate binding 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. Inserts at the 'B' site have no effect on sialic acid binding. {ECO:0000250, ECO:0000269\|PubMed:8522611}.
Ptm:		At synaptic junctions, cleaved at two conserved sites, alpha and beta, by neurotrypsin. Cleavage at the alpha-site produces the N- and C- terminal 110-kDa subunits. Further cleavage of the C-terminal at the beta site produces C-terminal fragments, C22 and C90, of 90 kDa and 22 kDa respectively (By similarity). {ECO:0000250}.
Ptm:		Proteolytically cleaved in vitro in both the N-terminal and C- terminal by several matrix metaloproteinases (MMPs). {ECO:0000269\|PubMed:22984437}.
Miscellaneous:		[Isoform 9]: Transmembrane isoform produced by usage of an alternative first exon. {ECO:0000305}.
Sequence caution:		Sequence=AAA48585.1; Type=Frameshift; Evidence={ECO:0000305};