SAP97

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 braincite journal |author=Müller BM, Kistner U, Veh RW, "et al" |title=Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein |journal=J. Neurosci. |volume=15 |issue=3 Pt 2 |pages=2354–66 |year=1995 |month=March |pmid=7891172 |doi= |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=7891172] . 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 [cite journal |author=Sans N, Racca C, Petralia RS, Wang YX, McCallum J, Wenthold RJ |title=Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway |journal=J. Neurosci. |volume=21 |issue=19 |pages=7506–16 |year=2001 |month=October |pmid=11567040 |doi= |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11567040] .

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.cite journal |author=Caruana G, Bernstein A |title=Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene |journal=Mol. Cell. Biol. |volume=21 |issue=5 |pages=1475–83 |year=2001 |month=March |pmid=11238884 |doi=10.1128/MCB.21.5.1475-1483.2001 |url=] cite journal |author=Mahoney ZX, Sammut B, Xavier RJ, "et al" |title=Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=52 |pages=19872–7 |year=2006 |month=December |pmid=17172448 |doi=10.1073/pnas.0609326103 |url=] Overexpression of SAP97 in mammalian neurons leads to increased synaptic strength. cite journal |author=Rumbaugh G, Sia GM, Garner CC, Huganir RL |title=Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons |journal=J. Neurosci. |volume=23 |issue=11 |pages=4567–76 |year=2003 |month=June |pmid=12805297 |doi= |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12805297 ]

tructure

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.cite journal |author=Lee S, Fan S, Makarova O, "et al" |title=A novel and conserved protein-protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia |journal=Mol. Cell. Biol. |volume=22 |issue=6 |pages=1778–91 |year=2002 |month=March |pmid=11865057 |doi= |url=http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=11865057] . There is also a myosin VI binding site near n-terminal which may be involved in the internalization of AMPAR. [cite journal |author=Wu H, Nash JE, Zamorano P, Garner CC |title=Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking |journal=J. Biol. Chem. |volume=277 |issue=34 |pages=30928–34 |year=2002 |month=August |pmid=12050163 |doi=10.1074/jbc.M203735200 |url=] [cite journal |author=Osterweil E, Wells DG, Mooseker MS |title=A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis |journal=J. Cell Biol. |volume=168 |issue=2 |pages=329–38 |year=2005 |month=January |pmid=15657400 |doi=10.1083/jcb.200410091 |url=]

Each of SAP97's PDZ domains have different binding partners, including the AMPAR subunit GluR1 [cite journal |author=Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW |title=SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit |journal=J. Biol. Chem. |volume=273 |issue=31 |pages=19518–24 |year=1998 |month=July |pmid=9677374 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=9677374] [cite journal |author=Cai C, Coleman SK, Niemi K, Keinänen K |title=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 |journal=J. Biol. Chem. |volume=277 |issue=35 |pages=31484–90 |year=2002 |month=August |pmid=12070168 |doi=10.1074/jbc.M204354200 |url=] 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, and to bind the protein 4.1N. The GK domain allows SAP97 to bind to GKAP/SAPAP-family proteins

References