DLG1

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.

DLG1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1PDR, 2M3M, 2OQS, 2X7Z, 3RL7, 3RL8, 3W9Y, 4AMH, 4G69
Identifiers
Aliases	DLG1, DLGH1, SAP-97, SAP97, dJ1061C18.1.1, hdlg, B130052P05Rik, E-dlg/SAP97, mKIAA4187, discs large homolog 1, scribble cell polarity complex component, discs large MAGUK scaffold protein 1
External IDs	OMIM: 601014 MGI: 107231 HomoloGene: 20869 GeneCards: DLG1
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q29 Start 197,042,560 bp[1] End 197,299,330 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 B2|16 22.4 cM Start 31,663,443 bp[2] End 31,875,129 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • phosphatase binding • phosphoprotein phosphatase activity • ion channel binding • cytoskeletal protein binding • protein C-terminus binding • ionotropic glutamate receptor binding • kinase binding • mitogen-activated protein kinase kinase binding • guanylate kinase activity • GO:0001948 protein binding • GO:0032947 molecular adaptor activity • protein kinase binding • L27 domain binding • ligand-gated ion channel activity • potassium channel regulator activity • cadherin binding • Ras guanyl-nucleotide exchange factor activity • structural constituent of postsynaptic density Cellular component • cytoplasm • cytosol • postsynaptic membrane • membrane • intercellular junction • bicellular tight junction • node of Ranvier • synapse • perinuclear region of cytoplasm • cytoplasmic side of plasma membrane • microtubule • cell nucleus • cell projection membrane • membrane raft • ionotropic glutamate receptor complex • extracellular exosome • Golgi apparatus • lateral plasma membrane • intercalated disc • neuromuscular junction • myelin sheath abaxonal region • lateral loop • endoplasmic reticulum membrane • basal lamina • MPP7-DLG1-LIN7 complex • sarcolemma • GO:0097483, GO:0097481 postsynaptic density • cell junction • basolateral plasma membrane • cell membrane • endoplasmic reticulum • immunological synapse • basement membrane • apical plasma membrane • neuron projection • postsynaptic density membrane • glutamatergic synapse Biological process • embryonic skeletal system morphogenesis • ureteric bud development • positive regulation of actin filament polymerization • positive regulation of potassium ion transport • negative regulation of p38MAPK cascade • amyloid precursor protein metabolic process • tissue morphogenesis • reproductive structure development • membrane raft organization • hard palate development • endothelial cell proliferation • smooth muscle tissue development • negative regulation of epithelial cell proliferation • regulation of sodium ion transmembrane transport • astral microtubule organization • actin filament organization • mitotic cell cycle checkpoint • receptor clustering • establishment or maintenance of cell polarity • negative regulation of T cell proliferation • branching involved in ureteric bud morphogenesis • regulation of myelination • cortical microtubule organization • establishment or maintenance of epithelial cell apical/basal polarity • GO:0022415 viral process • T cell cytokine production • T cell activation • peristalsis • receptor localization to synapse • negative regulation of protein kinase B signaling • regulation of NIK/NF-kappaB signaling • negative regulation of transcription from RNA polymerase II promoter • nervous system development • regulation of cell shape • establishment of centrosome localization • immunological synapse formation • GO:0033109 cortical actin cytoskeleton organization • protein localization • lens development in camera-type eye • cellular protein complex localization • bicellular tight junction assembly • positive regulation of cell proliferation • negative regulation of ERK1 and ERK2 cascade • activation of protein kinase activity • negative regulation of mitotic cell cycle • regulation of membrane potential • protein localization to plasma membrane • GDP metabolic process • ion transmembrane transport • protein dephosphorylation • GMP metabolic process • chemical synaptic transmission • regulation of ventricular cardiac muscle cell action potential • regulation of potassium ion import • regulation of voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization • regulation of potassium ion export across plasma membrane • MAPK cascade • cell-cell adhesion • maintenance of postsynaptic density structure • neurotransmitter receptor localization to postsynaptic specialization membrane • positive regulation of protein localization to plasma membrane • regulation of NMDA receptor activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1739	13383
Ensembl	ENSG00000075711	ENSMUSG00000022770
UniProt	Q12959	Q811D0
RefSeq (mRNA)	NM_001098424 NM_001204386 NM_001204387 NM_001204388 NM_001290983 NM_004087 NM_001363865 NM_001366203 NM_001366204 NM_001366205 NM_001366206 NM_001366207 NM_001366208 NM_001366209 NM_001366210 NM_001366211 NM_001366212 NM_001366213 NM_001366214 NM_001366215 NM_001366216 NM_001366217 NM_001366218 NM_001366219 NM_001366220 NM_001366221 NM_001366222	NM_001252433 NM_001252434 NM_001252435 NM_001252436 NM_007862 NM_001357281 NM_001357282
RefSeq (protein)	NP_001091894 NP_001191315 NP_001191316 NP_001191317 NP_001277912 NP_004078 NP_001350794 NP_001353132 NP_001353133 NP_001353134 NP_001353135 NP_001353136 NP_001353137 NP_001353138 NP_001353139 NP_001353140 NP_001353141 NP_001353142 NP_001353143 NP_001353144 NP_001353145 NP_001353146 NP_001353147 NP_001353148 NP_001353149 NP_001353150 NP_001353151	NP_001239362 NP_001239363 NP_001239364 NP_001239365 NP_031888 NP_001344210 NP_001344211
Location (UCSC)	Chr 3: 197.04 – 197.3 Mb	Chr 16: 31.66 – 31.88 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[5] 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.[6]

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.[7][8] Overexpression of SAP97 in mammalian neurons leads to increased synaptic strength.[9]

Clinical significance

Mutations in DLG1 are associated to Crohn's Disease.[10]

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.[11] There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR.[12][13]

Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1[14][15] 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[9] and to bind the protein 4.1N. The GK domain allows SAP97 to bind to GKAP/SAPAP-family proteins.

References

1. GRCh38: Ensembl release 89: ENSG00000075711 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022770 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Müller BM, Kistner U, Veh RW, Cases-Langhoff C, Becker B, Gundelfinger ED, Garner CC (Mar 1995). "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. PMID 7891172.
6. Sans N, Racca C, Petralia RS, Wang YX, McCallum J, Wenthold RJ (Oct 2001). "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. doi:10.1523/JNEUROSCI.21-19-07506.2001. PMID 11567040.
7. Caruana G, Bernstein A (Mar 2001). "Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene". Molecular and Cellular Biology. 21 (5): 1475–83. doi:10.1128/MCB.21.5.1475-1483.2001. PMC 86693. PMID 11238884.
8. Mahoney ZX, Sammut B, Xavier RJ, Cunningham J, Go G, Brim KL, Stappenbeck TS, Miner JH, Swat W (Dec 2006). "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. doi:10.1073/pnas.0609326103. PMC 1750896. PMID 17172448.
9. Rumbaugh G, Sia GM, Garner CC, Huganir RL (Jun 2003). "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. PMID 12805297.
10. Xu S, Zhou F, Tao J, Song L, Ng SC, Wang X, Chen L, Yi F, Ran Z, Zhou R, Xia B (2014). "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. doi:10.1371/journal.pone.0099807. PMC 4061034. PMID 24937328.
11. Lee S, Fan S, Makarova O, Straight S, Margolis B (Mar 2002). "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. doi:10.1128/MCB.22.6.1778-1791.2002. PMC 135599. PMID 11865057.
12. Wu H, Nash JE, Zamorano P, Garner CC (Aug 2002). "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. doi:10.1074/jbc.M203735200. PMID 12050163.
13. Osterweil E, Wells DG, Mooseker MS (Jan 2005). "A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis". The Journal of Cell Biology. 168 (2): 329–38. doi:10.1083/jcb.200410091. PMC 2171578. PMID 15657400.
14. Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW (Jul 1998). "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. doi:10.1074/jbc.273.31.19518. PMID 9677374.
15. Cai C, Coleman SK, Niemi K, Keinänen K (Aug 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". The Journal of Biological Chemistry. 277 (35): 31484–90. doi:10.1074/jbc.M204354200. PMID 12070168.

| volume = 25 | issue = 6 | pages = 542–53 | date = Jun 2003 | pmid = 12766944 | doi = 10.1002/bies.10286 }}

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