Biology:DLG1

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Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene.

SAP97 is a mammalian MAGUK-family member protein that is similar to the Drosophila protein Dlg1 (the protein is alternatively referred to as hDlg1, and the human gene is DLG1). SAP97 is expressed throughout the body in epithelial cells. In the brain it is involved in the trafficking of ionotropic receptors from the endoplasmic reticulum to the plasma membrane, and may be involved in the trafficking AMPAR during synaptic plasticity.

Function

SAP97 is expressed throughout the body in epithelial cells, including the kidney and brain.[1] There is some evidence that SAP97 regulates cell-to-cell adhesion during cell death, and may interact with HPV. In the brain, SAP97's function is involved in the trafficking of transmembrane receptors from the ER to the plasma membrane.[2]

SAP97's function has been investigated by reducing its expression by knockout or increasing its expression heterologously. Mice in which the SAP97 gene has been knocked out die perinatally, have a cleft palate, and deficiencies in renal function.[3][4] Overexpression of SAP97 in mammalian neurons leads to increased synaptic strength.[5]

Clinical significance

Mutations in DLG1 are associated to Crohn's Disease.[6]

Structure

SAP97's protein structure consists of an alternatively-spliced n-terminal domain, three PDZ domains, an SH3 domain, hook domain, I3 domain, and finally an inactive guanylate kinase (GK) domain. Each of these domains has specific interacting partners that help define SAP97's unique function.

The n-terminal of SAP97 can be alternatively spliced to contain a double-cysteine/palmitoylation site (α-isoform), or an L27 domain (β-isoform. The L27 domain is involved in SAP97 oligomerization with other SAP97 molecules, CASK, and other L27-domain-containing proteins.[7] There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR.[8][9]

Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1[10][11] for the first PDZ domain, and neuroligin for the last. SAP97's I3 domain is unique to SAP97 among the MAGUK family, and is known to regulate the post-synaptic localization of SAP97[5] and to bind the protein 4.1N. The GK domain allows SAP97 to bind to GKAP/SAPAP-family proteins.

References

  1. ↑ "Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein". The Journal of Neuroscience 15 (3 Pt 2): 2354–66. Mar 1995. doi:10.1523/JNEUROSCI.15-03-02354.1995. PMID 7891172. 
  2. ↑ "Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway". The Journal of Neuroscience 21 (19): 7506–16. Oct 2001. doi:10.1523/JNEUROSCI.21-19-07506.2001. PMID 11567040. 
  3. ↑ "Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene". Molecular and Cellular Biology 21 (5): 1475–83. Mar 2001. doi:10.1128/MCB.21.5.1475-1483.2001. PMID 11238884. 
  4. ↑ "Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter". Proceedings of the National Academy of Sciences of the United States of America 103 (52): 19872–7. Dec 2006. doi:10.1073/pnas.0609326103. PMID 17172448. Bibcode: 2006PNAS..10319872M. 
  5. ↑ 5.0 5.1 "Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons". The Journal of Neuroscience 23 (11): 4567–76. Jun 2003. doi:10.1523/JNEUROSCI.23-11-04567.2003. PMID 12805297. 
  6. ↑ "Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study". PLOS ONE 9 (6): e99807. 2014. doi:10.1371/journal.pone.0099807. PMID 24937328. Bibcode: 2014PLoSO...999807X. 
  7. ↑ "A novel and conserved protein-protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia". Molecular and Cellular Biology 22 (6): 1778–91. Mar 2002. doi:10.1128/MCB.22.6.1778-1791.2002. PMID 11865057. 
  8. ↑ "Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking". The Journal of Biological Chemistry 277 (34): 30928–34. Aug 2002. doi:10.1074/jbc.M203735200. PMID 12050163. 
  9. ↑ "A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis". The Journal of Cell Biology 168 (2): 329–38. Jan 2005. doi:10.1083/jcb.200410091. PMID 15657400. 
  10. ↑ "SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit". The Journal of Biological Chemistry 273 (31): 19518–24. Jul 1998. doi:10.1074/jbc.273.31.19518. PMID 9677374. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9677374. 
  11. ↑ "Selective binding of synapse-associated protein 97 to GluR-A alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionate receptor subunit is determined by a novel sequence motif". The Journal of Biological Chemistry 277 (35): 31484–90. Aug 2002. doi:10.1074/jbc.M204354200. PMID 12070168. 

Further reading

External links




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