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| | Figure 2: The domains of STRN. Isoform I is shown; amino acids are numbered according to Swiss-Prot description. |
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| Description | 780 amino acids (aa), 86.13 KDa (isoform I) and 731 amino acids, 80.76 KDa (isoform II). Striatin contains a high number of domains mediating protein-protein interactions. Domains:
aa 55-63 : Caveolin-binding; aa 53-120 : Coiled-coil; aa 149-166 : Calmodulin-binding; aa 461-500 : WD 1; aa 514-553 : WD 2; aa 567-606 : WD 3; aa 662-701 : WD 4; aa 704-743 : WD 5; aa 750-779 : WD 6 (30 aa only) (Isoform I, according to Swiss-Prot).
- Caveolin-binding domain: To bind caveolin, a caveolin-binding consensus is necessary: ΦXΦXXXXΦ, ΦXXXXΦXXΦ or ΦXΦXXXXΦXXΦ (Φ corresponding to aromatic amino acid) (Couet et al., 1997). Striatin contains the caveolin-binding consensus motif: LHFIQHEWARF, and binds directly caveolin-1 (Gaillard et al., 2001).
- Coiled-coil domain: Coiled-coil domains allow homo- and hetero-oligomerization. Oligomerization of striatin members is an obligatory step for the correct routing of the striatin family members to the dendritic spines (Gaillard et al., 2006).
- Ca2+ -calmodulin binding domain: Striatin binds calmodulin in a calcium-dependent manner. Ca2+ has a pleiotropic effect in cells. In dendritic spines, it plays a crucial role in the induction of most forms of synaptic potentiation and depression. Members of the striatin family could act as Ca2+ sensors in protein complexes, able to drive the delocalization of these complexes in different submembranous micro-domain according to the Ca2+ fluctuations (Benoist et al., 2006).
- WD-repeats (tryptophan-aspartate repeats): tend to form a propeller structure, stable platform that reversibly interacts with several proteins. The WD-repeat domain enables proteins to establish multiple protein-protein interactions. Striatin possesses at least 6 WD-repeats (eight were reported previously). |
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| | Figure 3: WD-repeats propeller structure. |
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| Expression | Widely expressed (heart, various digestive organs, kidney, and others (Breitman et al., 2008)), but mainly in the nervous system. All members of the striatin family are expressed in the central nervous system and in the peripheral nervous system (Blondeau et al., 2003). Striatin is found in dendrites, on the post-synaptic side, in the post-synaptic densities of neuronal dendritic spines, particularly in the striatum. |
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| | Figure 4: ModBase predicted comparative 3D structure (Front / Top / Side). Reproduced courtesy UCSC Genome Browser website. |
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| Localisation | Found in the cytosol, and also found associated with membranes. |
| Function | Striatin, like other striatin family members, binds many proteins, and forms multi-protein complexes. Striatin family members are scaffolding proteins involved in signaling and trafficking in a Ca2+ dependant manner, exhibiting a dual role in endocytic process and signaling.
- Relation with caveolins: striatin directly binds caveolin-1 (Gaillard et al., 2001), a palmitoylated protein involved in caveolae and lipid rafts. Caveolins are scaffolding proteins, the main components of caveolae. Caveolae start as plasma membrane pits and form vesicles in the cytoplasm. Caveolae represent one mode of endocytosis (a clathrin independent mode of endocytosis). Caveolins also have the capacity to bind cholesterol, and are involved in signal transduction processes by directly interacting with a great number of signaling proteins such as nitric oxide synthases, G-proteins, protein tyrosine kinases, and H-Ras (Krajewska et al., 2004). Caveolin-1 is concentrated within dendritic spines of synapses in activity.
- Role in synaptic transmission: striatin down regulation in embryonic motoneurones results in the arrest of dendritic growth, but not in axon growth impairement (Bartoli et al., 1999).
Members of the striatin family have been shown to interact with phocein, a protein involved in clathrin- and dynamin-dependent membrane dynamics (Baillat et al., 2001, Haeberle et al., 2006). Phocein has been implicated in vesicular trafficking, acting in particular in the endocytic process in Purkinje cell dendritic spines (Bailly et al., 2007).
The coiled-coil domain of the striatin family members seems crucial for homo- and hetero-oligomerization of these proteins. Striatin family members are often co-expressed in the neurons. The coiled-coil domain also plays an essential role in the targeting of STRN3 within spines (Gaillard et al., 2006).
- Role in the "non-genomic" estrogen-mediated activation of downstream signaling pathways: in vascular endothelial cells, estrogen receptor (ER) alpha is targeted by striatin (or by STRN3, there is a controversy in this) to a module in membrane caveolae that enables estrogen to activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 (PI3K)-Akt kinase pathways, and endothelial NO synthase (eNOS). Striatin (or STRN3) directly binds ER alpha and anchors ER alpha to the membrane and organizes the ER alpha-eNOS membrane signaling complex (Lu et al., 2004) (Note: estrogens also act in a "genomic manner", as transcrition factors, regulating gene expression).
- Cell lines: In NIH3T3 cells, striatin and STRN3 form stable complexes with protein phosphatase 2A (PP2A), a multifunctional serine/threonine phosphatase, critical to many cellular processes (Moreno et al., 2000), including presence in the b-catenin degradation complex, leading to degradation of b-catenin and inhibition of Wnt signaling, but also F-actin binding and regulation and aPKC (a member of the Par complex) regulation.
In HEK293Tcells, striatin binds APC (Breitman et al., 2008). APC is a a multi-function protein e.g.: negative WNT signaling pathway regulation, preventing transcription of Wnt target genes; modulation of the actin cytoskeleton and influence on cell adhesion and cell motility, binding to microtubules inducing stabilization of their ends; interaction with the disks large homologs, which are scaffolding proteins. The APC armadillo repeat domain binds the WD-repeats of striatin and both proteins co-localize at epithelial cell to cell junctions and seem to play a role in junctional organization, since their depletion resulted in a F-actin network fragmentation.
- Neurones and epithelial cells: it may be possible that Striatin and APC (and perhaps PP2A) are involved in the Par complex (PAR-3, PAR-6 and aPKC), a protein complex crucial for neurite, as well as for epithelial cell, polarization (Breitman et al., 2008). |
| Homology | Other members of the striatin family, i.e.: STRN3 (SG2NA) (14q12) and STRN4 (zinedin) (19q13.2), are 80% and 75% homologous to STRN. |
| Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. |
| Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP. |
| J Biol Chem. 1997 Mar 7; 272(10): 6525-33. |
| PMID 9045678 |
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| Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity. |
| Bartoli M, Ternaux JP, Forni C, Portalier P, Salin P, Amalric M, Monneron A. |
| J Neurobiol. 1999 Aug; 40(2): 234-43. |
| PMID 10413453 |
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| WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. |
| Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS, Pallas DC. |
| J Biol Chem. 2000 Feb 25; 275(8): 5257-63. |
| PMID 10681496 |
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| Molecular cloning and characterization of phocein, a protein found from the Golgi complex to dendritic spines. |
| Baillat G, Moqrich A, Castets F, Baude A, Bailly Y, Benmerah A, Monneron A. |
| Mol Biol Cell. 2001 Mar; 12(3): 663-73. |
| PMID 11251078 |
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| Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1. |
| Gaillard S, Bartoli M, Castets F, Monneron A. |
| FEBS Lett. 2001 Nov 9; 508(1): 49-52. |
| PMID 11707266 |
| |
| Expression and distribution of phocein and members of the striatin family in neurones of rat peripheral ganglia. |
| Blondeau C, Gaillard S, Ternaux JP, Monneron A, Baude A. |
| Histochem Cell Biol. 2003 Feb; 119(2): 131-8. |
| PMID 12610732 |
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| Caveolins: structure and function in signal transduction. |
| Krajewska WM, Maslowska I. |
| Cell Mol Biol Lett. 2004; 9(2): 195-220. (Review) |
| PMID 15213803 |
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| Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. |
| Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH. |
| Proc Natl Acad Sci U S A. 2004 Dec 7; 101(49): 17126-31. |
| PMID 15569929 |
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| Immunogold localization of phocein in dendritic spines. |
| Haeberle AM, Castets F, Bombarde G, Baillat G, Bailly Y. |
| J Comp Neurol. 2006 Mar 20; 495(3): 336-50. |
| PMID 16440294 |
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| Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain. |
| Gaillard S, Bailly Y, Benoist M, Rakitina T, Kessler JP, Fronzaroli-Molinieres L, Dargent B, Castets F. |
| Traffic. 2006 Jan; 7(1): 74-84. |
| PMID 16445688 |
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| The striatin family: a new signaling platform in dendritic spines. |
| Benoist M, Gaillard S, Castets F. |
| J Physiol Paris. 2006 Mar-May;99(2-3):146-53. Epub 2006 Feb 7. (Review) |
| PMID 16460920 |
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| Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain. |
| Gaillard S, Bailly Y, Benoist M, Rakitina T, Kessler JP, Fronzaroli-Molinières L, Dargent B, Castets F. |
| Traffic. 2006 Jan; 7(1): 74-84. |
| PMID 16445688 |
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| Phocein: A potential actor in vesicular trafficking at Purkinje cell dendritic spines. |
| Bailly YJ, Castets F. |
| Cerebellum. 2007 Feb 23: 1-9. |
| PMID 17853115 |
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| Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia. |
| Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, Minervini MM, Stewart J, Reiter A, Cross NC. |
| Br J Haematol. 2007 Jul; 138(1): 77-81. |
| PMID 17555450 |
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| The armadillo repeat domain of the APC tumor suppressor protein interacts with Striatin family members. |
| Breitman M, Zilberberg A, Caspi M, Rosin-Arbesfeld R. |
| Biochim Biophys Acta. 2008 May 3. |
| PMID 18502210 |
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