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the activity of the associated catalytic subunit, and conferring PP1 isoform selectivity [Bollen,
2001].
Spinophilin also contains a single consensus sequence in PDZ, amino acids 494-585
[Allen et al., 1997]. The structure of the spinophilin and neurabin 1 PDZ domains have been
recently solved by NMR spectroscopy. Both PDZ domains directly bind to carboxy-terminal
peptides derived from glutamatergic AMPA and NMDA receptor [Kelker et al., 2007].
Sequence analysis predicted that the carboxy-terminal region of spinophilin (amino acids
664-814) forms 3 coiled-coil domains. Neurabins were observed as multimeric species in
vitro and in vivo. Spinophilin and neurabin 1 homo- and hetero-dimerize via their carboxy-
terminal coiled-coil domains [MacMillan et al., 1999; Oliver et al., 2002].
Consensus sequences for phosphorylation by several PKs, including cAMP-dependent
PK (PKA), Ca 2+ /calmodulin-dependent PK II (CaMKII), cyclin-dependent PK5 (Cdk5),
extracellular-signal regulated PK (ERK) and protein tyrosine kinases were observed in
spinophilin. Two major sites of phosphorylation for PKA (Ser-177 not conserved in human,
and Ser-94) and two others sites for CaMKII phosphorylation (Ser-100 not conserved in
neurabin 1, and Ser-116) were located within and near the F-actin-binding domain of
spinophilin. Spinophilin is phosphorylated in intact cells by PKA at Ser-94 and Ser-177 and
by CaMKII at Ser-100 [Hsieh-Wilson et al., 2003; Grossman et al., 2004]. Moreover
neurabins can be phosphorylated in vitro and in intact cells by Cdk5 on Ser-17 and ERK2
(MAPK1) on Ser-15 and Ser-205, phosphoSer-17 being abundant in neuronal cells [Futter et
al., 2005]. Two potential tyrosine phosphorylation sites lie within the coiled-coil regions of
spinophilin and 2 others within a region adjacent to the PDZ domain.
Neurabin 1 consists of 1095 amino acids and contains one F-actin- and a PP1c-binding
domains, a PDZ, a coiled-coil and a sterile alpha motif (SAM) domains at its [Nakanishi et
al., 1997]. The structure of the neurabin 1 SAM domain was recently determined by NMR
spectroscopy [Ju et al., 2007]. This SAM domain is a monomer in solution and must function
via protein-protein interaction with other proteins. Primary sequence identity between
spinophilin and neurabin 1 is: PDZ domain 86 %, PP1c binding domain 81 %, coiled-coil
domain 63 % and F-actin binding domain 40 %.
3. L OCALIZATION OF S PINOPHILIN IN THE
C ENTRAL N ERVOUS S YSTEM
Spinophilin expression in brain appeared to be differently regulated during mouse life,
with high levels observed after birth and in the adult brain [Tsukada et al., 2003]. Spinophilin
was enriched in cerebral cortex, caudatoputamen, hippocampal formation, and cerebellum
[Ouimet et al., 2004]. Subcellular studies showed that spinophilin was localized
predominantly in dendritic spines [Ouimet et al., 2004; Mully et al., 2004].
Dendritic spines are small membranous protusions from the central stalk of a dendrite,
containing a bulbous head and a thin neck. Dendritic spines contain the majority of excitatory
synapses and each spine has a single synapse. The localization of spinophilin within dendritic
spines may be controlled by phosphorylation. Two localization domains of spinophilin were
revealed within dendritic spines. One, consisting of the PSD and the subjacent 100 nm of
spinoplasm, contained the highest density of label. Unphosphorylated spinophilin was
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