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Discs, large homolog 1 (Drosophila)

PDB rendering based on 1iu0.
Available structures
1iu0, 1iu2, 1kef, 1pdr, 1rgr, 1rso, 1zok, 2awu, 2aww, 2awx, 2g2l, 2i0i, 2i0l
Identifiers
Symbols DLG1; DKFZp761P0818; DLGH1; SAP97; dJ1061C18.1.1; hdlg
External IDs OMIM601014 MGI107231 HomoloGene20869 GeneCards: DLG1 Gene
RNA expression pattern
PBB GE DLG1 202515 at tn.png
PBB GE DLG1 202514 at tn.png
PBB GE DLG1 202516 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1739 13383
Ensembl ENSG00000075711 ENSMUSG00000022770
UniProt Q12959 Q3TPP5
RefSeq (mRNA) NM_004087 XM_001000012
RefSeq (protein) NP_004078 XP_001000012
Location (UCSC) Chr 3:
198.26 - 198.51 Mb
Chr 16:
31.58 - 31.79 Mb
PubMed search [1] [2]

Discs, large homolog 1 (Drosophila), also known as DLG1 or SAP97, is a protein which 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.

Contents

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]

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.[6]. There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR.[7][8]

Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1[9][10] 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. ^ Müller BM, Kistner U, Veh RW, et al. (March 1995). "Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein". J. Neurosci. 15 (3 Pt 2): 2354–66. PMID 7891172. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=7891172.  
  2. ^ Sans N, Racca C, Petralia RS, Wang YX, McCallum J, Wenthold RJ (October 2001). "Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway". J. Neurosci. 21 (19): 7506–16. PMID 11567040. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11567040.  
  3. ^ Caruana G, Bernstein A (March 2001). "Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene". Mol. Cell. Biol. 21 (5): 1475–83. doi:10.1128/MCB.21.5.1475-1483.2001. PMID 11238884.  
  4. ^ Mahoney ZX, Sammut B, Xavier RJ, et al. (December 2006). "Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter". Proc. Natl. Acad. Sci. U.S.A. 103 (52): 19872–7. doi:10.1073/pnas.0609326103. PMID 17172448.  
  5. ^ a b Rumbaugh G, Sia GM, Garner CC, Huganir RL (June 2003). "Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons". J. Neurosci. 23 (11): 4567–76. PMID 12805297. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12805297.  
  6. ^ Lee S, Fan S, Makarova O, et al. (March 2002). "A novel and conserved protein-protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia". Mol. Cell. Biol. 22 (6): 1778–91. doi:10.1128/MCB.22.6.1778-1791.2002. PMID 11865057. http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=11865057.  
  7. ^ Wu H, Nash JE, Zamorano P, Garner CC (August 2002). "Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking". J. Biol. Chem. 277 (34): 30928–34. doi:10.1074/jbc.M203735200. PMID 12050163.  
  8. ^ Osterweil E, Wells DG, Mooseker MS (January 2005). "A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis". J. Cell Biol. 168 (2): 329–38. doi:10.1083/jcb.200410091. PMID 15657400.  
  9. ^ Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW (July 1998). "SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit". J. Biol. Chem. 273 (31): 19518–24. doi:10.1074/jbc.273.31.19518. PMID 9677374. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9677374.  
  10. ^ Cai C, Coleman SK, Niemi K, Keinänen K (August 2002). "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". J. Biol. Chem. 277 (35): 31484–90. doi:10.1074/jbc.M204354200. PMID 12070168.  

Further reading

  • Humbert P, Russell S, Richardson H (2003). "Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer.". Bioessays 25 (6): 542–53. doi:10.1002/bies.10286. PMID 12766944.  
  • Mukherjee A, Varma SK, Natarajan K (1972). "Ankle joint instability in poliomyelitis.". Indian journal of pediatrics 39 (289): 37–8. PMID 5024025.  
  • Kim E, Niethammer M, Rothschild A, et al. (1995). "Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases.". Nature 378 (6552): 85–8. doi:10.1038/378085a0. PMID 7477295.  
  • Lue RA, Marfatia SM, Branton D, Chishti AH (1994). "Cloning and characterization of hdlg: the human homologue of the Drosophila discs large tumor suppressor binds to protein 4.1.". Proc. Natl. Acad. Sci. U.S.A. 91 (21): 9818–22. PMID 7937897.  
  • Niethammer M, Kim E, Sheng M (1996). "Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases.". J. Neurosci. 16 (7): 2157–63. PMID 8601796.  
  • Azim AC, Knoll JH, Marfatia SM, et al. (1997). "DLG1: chromosome location of the closest human homologue of the Drosophila discs large tumor suppressor gene.". Genomics 30 (3): 613–6. doi:10.1006/geno.1995.1286. PMID 8825652.  
  • Lue RA, Brandin E, Chan EP, Branton D (1997). "Two independent domains of hDlg are sufficient for subcellular targeting: the PDZ1-2 conformational unit and an alternatively spliced domain.". J. Cell Biol. 135 (4): 1125–37. PMID 8922391.  
  • Takeuchi M, Hata Y, Hirao K, et al. (1997). "SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density.". J. Biol. Chem. 272 (18): 11943–51. PMID 9115257.  
  • Horio Y, Hibino H, Inanobe A, et al. (1997). "Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90.". J. Biol. Chem. 272 (20): 12885–8. PMID 9148889.  
  • Lee SS, Weiss RS, Javier RT (1997). "Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein.". Proc. Natl. Acad. Sci. U.S.A. 94 (13): 6670–5. PMID 9192623.  
  • Satoh K, Yanai H, Senda T, et al. (1997). "DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95.". Genes Cells 2 (6): 415–24. PMID 9286858.  
  • Hanada T, Lin L, Chandy KG, et al. (1997). "Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes.". J. Biol. Chem. 272 (43): 26899–904. PMID 9341123.  
  • Reuver SM, Garner CC (1998). "E-cadherin mediated cell adhesion recruits SAP97 into the cortical cytoskeleton.". J. Cell. Sci. 111 ( Pt 8): 1071–80. PMID 9512503.  
  • Leonard AS, Davare MA, Horne MC, et al. (1998). "SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit.". J. Biol. Chem. 273 (31): 19518–24. PMID 9677374.  
  • Deguchi M, Hata Y, Takeuchi M, et al. (1998). "BEGAIN (brain-enriched guanylate kinase-associated protein), a novel neuronal PSD-95/SAP90-binding protein.". J. Biol. Chem. 273 (41): 26269–72. PMID 9756850.  
  • Brenman JE, Topinka JR, Cooper EC, et al. (1998). "Localization of postsynaptic density-93 to dendritic microtubules and interaction with microtubule-associated protein 1A.". J. Neurosci. 18 (21): 8805–13. PMID 9786987.  
  • Bassand P, Bernard A, Rafiki A, et al. (1999). "Differential interaction of the tSXV motifs of the NR1 and NR2A NMDA receptor subunits with PSD-95 and SAP97.". Eur. J. Neurosci. 11 (6): 2031–43. PMID 10336672.  
  • Firestein BL, Firestein BL, Brenman JE, et al. (2000). "Cypin: a cytosolic regulator of PSD-95 postsynaptic targeting.". Neuron 24 (3): 659–72. PMID 10595517.  
  • Hibino H, Inanobe A, Tanemoto M, et al. (2000). "Anchoring proteins confer G protein sensitivity to an inward-rectifier K(+) channel through the GK domain.". EMBO J. 19 (1): 78–83. doi:10.1093/emboj/19.1.78. PMID 10619846.  
  • Adey NB, Huang L, Ormonde PA, et al. (2000). "Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and stimulates PDZ binding.". Cancer Res. 60 (1): 35–7. PMID 10646847.  
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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]

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.[6]. There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR.[7][8]

Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1[9][10] 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. Müller BM, Kistner U, Veh RW, et al. (March 1995). "Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein". J. Neurosci. 15 (3 Pt 2): 2354–66. PMID 7891172. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=7891172. 
  2. Sans N, Racca C, Petralia RS, Wang YX, McCallum J, Wenthold RJ (October 2001). "Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway". J. Neurosci. 21 (19): 7506–16. PMID 11567040. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11567040. 
  3. Caruana G, Bernstein A (March 2001). "Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene". Mol. Cell. Biol. 21 (5): 1475–83. doi:10.1128/MCB.21.5.1475-1483.2001. PMID 11238884. 
  4. Mahoney ZX, Sammut B, Xavier RJ, et al. (December 2006). "Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter". Proc. Natl. Acad. Sci. U.S.A. 103 (52): 19872–7. doi:10.1073/pnas.0609326103. PMID 17172448. 
  5. 5.0 5.1 Rumbaugh G, Sia GM, Garner CC, Huganir RL (June 2003). "Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons". J. Neurosci. 23 (11): 4567–76. PMID 12805297. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12805297. 
  6. Lee S, Fan S, Makarova O, et al. (March 2002). "A novel and conserved protein-protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia". Mol. Cell. Biol. 22 (6): 1778–91. doi:10.1128/MCB.22.6.1778-1791.2002. PMID 11865057. http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=11865057. 
  7. Wu H, Nash JE, Zamorano P, Garner CC (August 2002). "Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking". J. Biol. Chem. 277 (34): 30928–34. doi:10.1074/jbc.M203735200. PMID 12050163. 
  8. Osterweil E, Wells DG, Mooseker MS (January 2005). "A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis". J. Cell Biol. 168 (2): 329–38. doi:10.1083/jcb.200410091. PMID 15657400. 
  9. Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW (July 1998). "SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit". J. Biol. Chem. 273 (31): 19518–24. doi:10.1074/jbc.273.31.19518. PMID 9677374. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9677374. 
  10. Cai C, Coleman SK, Niemi K, Keinänen K (August 2002). "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". J. Biol. Chem. 277 (35): 31484–90. doi:10.1074/jbc.M204354200. PMID 12070168. 

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