Agrin
Developmental stage
All (z+), (z-), (y+) and (y-) isoforms present throughout muscle fiber basal laminae in neonatal animals.
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 (By similarity).
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. This neuron-specific (z+) isoform is a 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 transmembrane agrin (TM-agrin) isoform, 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 2 and isoform 3: these isoforms lacking the 'z' insert (z0) are muscle-specific, have no AChR clustering ability and may be involved in nervous system endothelial cell differentiation.
Agrin N-terminal 110 kDa subunit
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.
Post-translational modifications
Contains heparan and chondroitin sulfate chains and alpha-dystroglycan as well as N-linked and O-linked oligosaccharides. 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). 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.
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). Cleavage is developmentally regulated. In developing brain, neurotrypsin-mediated cleavage occurs mainly during late fetal days and in the first postnatal week.
Tissue Specificity
Expressed in central nervous system (CNS) synapses such as in the cerebral cortex and hippocampus. Localizes to basal lamina of hippocampal blood vessels. Both (z+) and (z-) isoforms found in kidney, heart and cerebral vasculature.
Cellular localization
- Synapse
- Cell membrane
- Single-pass type II membrane protein
Alternative names
Agrin