Biology:Agrin

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Agrin NtA domain
Identifiers
SymbolNtA
PfamPF03146
InterProIPR004850
SCOP21jc7 / SCOPe / SUPFAM

Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. In humans, this protein is encoded by the AGRN gene.[1][2][3]

This protein has nine domains homologous to protease inhibitors.[4] It may also have functions in other tissues and during other stages of development. It is a major proteoglycan component in the glomerular basement membrane and may play a role in the renal filtration and cell-matrix interactions.[5]

Agrin functions by activating the MuSK protein (for Muscle-Specific Kinase), [6] which is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction.[7] Agrin is required to activate MuSK.[8] Agrin is also required for neuromuscular junction formation.[9]

Discovery

Agrin was first identified by the U.J. McMahan laboratory, Stanford University.[10]

Mechanism of action

During development in humans, the growing end of motor neuron axons secrete a protein called agrin.[11] When secreted, agrin binds to several receptors on the surface of skeletal muscle. The receptor which appears to be required for the formation of the neuromuscular junction (NMJ) is called the MuSK receptor (Muscle specific kinase).[12][13] MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself and on proteins that bind the cytoplasmic domain of the receptor.

In addition to MuSK, agrin binds several other proteins on the surface of muscle, including dystroglycan and laminin. It is seen that these additional binding steps are required to stabilize the NMJ.

The requirement for Agrin and MuSK in the formation of the NMJ was demonstrated primarily by knockout mouse studies. In mice that are deficient for either protein, the neuromuscular junction does not form.[14] Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example, MuSK also binds a protein called "dishevelled" (Dvl), which is in the Wnt signalling pathway. Dvl is additionally required for MuSK-mediated clustering of AChRs, since inhibition of Dvl blocks clustering.

Signaling

The nerve secretes agrin, resulting in phosphorylation of the MuSK receptor.

It seems that the MuSK receptor recruits casein kinase 2, which is required for clustering.[15]

A protein called rapsyn is then recruited to the primary MuSK scaffold, to induce the additional clustering of acetylcholine receptors (AChR). This is thought of as the secondary scaffold. A protein called Dok-7 has shown to be additionally required for the formation of the secondary scaffold; it is apparently recruited after MuSK phosphorylation and before acetylcholine receptors are clustered.

Structure

There are three potential heparan sulfate (HS) attachment sites within the primary structure of agrin, but it is thought that only two of these actually carry HS chains when the protein is expressed.

In fact, one study concluded that at least two attachment sites are necessary by inducing synthetic agents. Since agrin fragments induce acetylcholine receptor aggregation as well as phosphorylation of the MuSK receptor, researchers spliced them and found that the variant did not trigger phosphorylation. It has also been shown that the G3 domain of agrin is very plastic, meaning it can discriminate between binding partners for a better fit.[16]

Heparan sulfate glycosaminoglycans covalently linked to the agrin protein have been shown to play a role in the clustering of AChR. Interference in the correct formation of heparan sulfate through the addition of chlorate to skeletal muscle cell culture results in a decrease in the frequency of spontaneous acetylcholine receptor (AChR) clustering. It may be that rather than solely binding directly to the agrin protein core a number of components of the secondary scaffold may also interact with its heparan sulfate side-chains.[17]

A role in the retention of anionic macromolecules within the vasculature has also been suggested for agrin-linked HS at the glomerular or alveolar basement membrane.

Functions

Agrin may play an important role in the basement membrane of the microvasculature as well as in synaptic plasticity. Also, agrin may be involved in blood–brain barrier (BBB) formation and/or function [18][19] and it influences Aβ homeostasis.[20]

Research

Agrin is investigated in relation with osteoarthritis.[21][22] In addition, by its ability to activate the Hippo signaling pathway, agrin is emerging as a key proteoglycan in the tumor microenvironment.[23]

Clinical significance

AGRN gene mutation leads to congenital myasthenic syndromes[24][25][26] and myasthenia gravis.[27][28]

A recent genome-wide association study (GWAS) has found that genetic variations in AGRN are associated with late-onset sporadic Alzheimer’s disease (LOAD). These genetic variations alter β-amyloid homeostasis contributing to its accumulation and plaque formation.[29][30]

References

  1. ↑ "Structure and expression of a rat agrin". Neuron 6 (5): 811–823. May 1991. doi:10.1016/0896-6273(91)90177-2. PMID 1851019. 
  2. ↑ "Agrin in the developing CNS: new roles for a synapse organizer". News in Physiological Sciences 17 (5): 207–212. October 2002. doi:10.1152/nips.01390.2002. PMID 12270958. 
  3. ↑ "Primary structure and high expression of human agrin in basement membranes of adult lung and kidney". European Journal of Biochemistry 254 (1): 123–128. May 1998. doi:10.1046/j.1432-1327.1998.2540123.x. PMID 9652404. 
  4. ↑ "Agrin is a heparan sulfate proteoglycan". The Journal of Biological Chemistry 270 (7): 3392–3399. February 1995. doi:10.1074/jbc.270.7.3392. PMID 7852425. 
  5. ↑ "Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane". The Journal of Histochemistry and Cytochemistry 46 (1): 19–27. January 1998. doi:10.1177/002215549804600104. PMID 9405491. 
  6. ↑ "Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury". Neuron 15 (3): 573–584. Sep 1995. doi:10.1016/0896-6273(95)90146-9. PMID 7546737. 
  7. ↑ "The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo". Cell 85 (4): 501–512. May 1996. doi:10.1016/s0092-8674(00)81251-9. PMID 8653786. 
  8. ↑ "Agrin acts via a MuSK receptor complex". Cell 85 (4): 513–523. May 1996. doi:10.1016/s0092-8674(00)81252-0. PMID 8653787. 
  9. ↑ "Defective neuromuscular synaptogenesis in agrin-deficient mutant mice". Cell 85 (4): 525–535. May 1996. doi:10.1016/s0092-8674(00)81253-2. PMID 8653788. 
  10. ↑ "Chapter 32 Agrin". Neural Regeneration. Progress in Brain Research. 71. 1987. pp. 391–396. doi:10.1016/S0079-6123(08)61840-3. ISBN 978-0-444-80814-1. 
  11. ↑ "Induction, assembly, maturation and maintenance of a postsynaptic apparatus". Nature Reviews. Neuroscience 2 (11): 791–805. November 2001. doi:10.1038/35097557. PMID 11715056. 
  12. ↑ "Agrin acts via a MuSK receptor complex". Cell 85 (4): 513–523. May 1996. doi:10.1016/S0092-8674(00)81252-0. PMID 8653787. 
  13. ↑ "Agrin receptors at the skeletal neuromuscular junction". Annals of the New York Academy of Sciences 841 (1): 1–13. May 1998. doi:10.1111/j.1749-6632.1998.tb10905.x. PMID 9668217. Bibcode: 1998NYASA.841....1S. 
  14. ↑ "Defective neuromuscular synaptogenesis in agrin-deficient mutant mice". Cell 85 (4): 525–535. May 1996. doi:10.1016/S0092-8674(00)81253-2. PMID 8653788. 
  15. ↑ "Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction". Genes & Development 20 (13): 1800–1816. July 2006. doi:10.1101/gad.375206. PMID 16818610. 
  16. ↑ PDB: 1PZ7​; "Modulation of agrin function by alternative splicing and Ca2+ binding". Structure 12 (3): 503–515. March 2004. doi:10.1016/j.str.2004.02.001. PMID 15016366. 
  17. ↑ "Reduced glycosaminoglycan sulfation diminishes the agrin signal transduction pathway". Developmental Neuroscience 26 (1): 1–10. 2004. doi:10.1159/000080706. PMID 15509893. 
  18. ↑ "Agrin in Alzheimer's disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma". Proceedings of the National Academy of Sciences of the United States of America 96 (11): 6468–6472. May 1999. doi:10.1073/pnas.96.11.6468. PMID 10339611. Bibcode: 1999PNAS...96.6468D. 
  19. ↑ "Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier". The Neuroscientist 15 (2): 180–193. April 2009. doi:10.1177/1073858408329509. PMID 19307424. 
  20. ↑ "Changes in brain β-amyloid deposition and aquaporin 4 levels in response to altered agrin expression in mice". Journal of Neuropathology and Experimental Neurology 70 (12): 1124–1137. December 2011. doi:10.1097/NEN.0b013e31823b0b12. PMID 22082664. 
  21. ↑ Thorup, Anne-Sophie; Dell'Accio, Francesco; Eldridge, Suzanne E. (16 September 2020). "Regrowing knee cartilage: new animal studies show promise" (in en). http://theconversation.com/regrowing-knee-cartilage-new-animal-studies-show-promise-145430. 
  22. ↑ "Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis". Science Translational Medicine 12 (559): eaax9086. September 2020. doi:10.1126/scitranslmed.aax9086. PMID 32878982. 
  23. ↑ "Linking Extracellular Matrix Agrin to the Hippo Pathway in Liver Cancer and Beyond". Cancers 10 (2): 45. February 2018. doi:10.3390/cancers10020045. PMID 29415512. 
  24. ↑ "AGRN Gene Mutation Leads to Congenital Myasthenia Syndromes: A Pediatric Case Report and Literature Review". Neuropediatrics 51 (5): 364–367. October 2020. doi:10.1055/s-0040-1708534. PMID 32221959. 
  25. ↑ "Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner". JCI Insight 5 (7): 132023. April 2020. doi:10.1172/jci.insight.132023. PMID 32271162. 
  26. ↑ "Novel SEA and LG2 Agrin mutations causing congenital Myasthenic syndrome". Orphanet Journal of Rare Diseases 12 (1): 182. December 2017. doi:10.1186/s13023-017-0732-z. PMID 29258548. 
  27. ↑ "Autoantibodies to agrin in myasthenia gravis patients". PLOS ONE 9 (3): e91816. 2014-03-14. doi:10.1371/journal.pone.0091816. PMID 24632822. Bibcode: 2014PLoSO...991816Z. 
  28. ↑ "Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis". Annals of the New York Academy of Sciences 1413 (1): 126–135. February 2018. doi:10.1111/nyas.13573. PMID 29377176. Bibcode: 2018NYASA1413..126Y. 
  29. ↑ "A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease". Nature Genetics 53 (9): 1276–1282. September 2021. doi:10.1038/s41588-021-00921-z. PMID 34493870. PMC 10243600. https://research.vu.nl/en/publications/61f01aa9-6dc7-4213-be2a-d3fe622db488. 
  30. ↑ "Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology". Molecular Neurodegeneration 16 (1): 59. August 2021. doi:10.1186/s13024-021-00465-0. PMID 34454574. 

Further reading

External links



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