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Phospho-regulated Drosophila adducin is a determinant of synaptic plasticity in a complex with Dlg and PIP2 at the larval neuromuscular junction.

Wang SJ, Tsai A, Wang M, Yoo S, Kim HY, Yoo B, Chui V, Kisiel M, Stewart B, Parkhouse W, Harden N, Krieger C - Biol Open (2014)

Bottom Line: We provide evidence that Hts promotes the phosphorylation and delocalization of Dlg at the NMJ through regulation of the transcript distribution of the PAR-1 and CaMKII kinases in the muscle.We also show that Hts interactions with Dlg and PIP2 are impeded through phosphorylation of the MARCKS-homology domain.These results are further evidence that Hts is a signaling-responsive regulator of synaptic plasticity in Drosophila.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.

No MeSH data available.


Related in: MedlinePlus

Phosphorylation of the MARCKS-homology domain regulates Hts' interactions with Dlg and PIP2 at the postsynaptic membrane of larval NMJs.Schematic of a larval NMJ viewed in cross-section, with the presynaptic side shown at the top and the postsynaptic side shown at the bottom. (A) At the postsynaptic membrane, Dlg localizes to spectrin-actin complexes. Homophilic adhesion between Fasciclin 2 (Fas2) transmembrane proteins links the presynaptic and postsynaptic sides, with the intracellular C-terminal domains anchored to the first and second PDZ domains of Dlg. Hts is in a complex with Dlg at the postsynaptic membrane, though the interaction may not be direct. Hts also binds to PIP2 via the MARCKS-homology domain. (B) Hts promotes the accumulation of par-1 and camkII transcripts in the muscle cytoplasm through an as of yet identified mechanism. PAR-1 and CaMKII phosphorylate Dlg at serine 797 in the GUK domain and serine 48 in one of the PDZ domains respectively. Phosphorylation at either one of these sites disrupts Dlg postsynaptic targeting. (C) Phosphorylation of serine 704 in the MARCKS-homology domain translocates Hts away from the postsynaptic membrane and hinders Hts' ability to regulate Dlg localization, presumably through the control of PAR-1 and CaMKII at the transcriptional level. Phosphorylation of the MARCKS-homology domain also inhibits Hts' ability to bind to PIP2.
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f08: Phosphorylation of the MARCKS-homology domain regulates Hts' interactions with Dlg and PIP2 at the postsynaptic membrane of larval NMJs.Schematic of a larval NMJ viewed in cross-section, with the presynaptic side shown at the top and the postsynaptic side shown at the bottom. (A) At the postsynaptic membrane, Dlg localizes to spectrin-actin complexes. Homophilic adhesion between Fasciclin 2 (Fas2) transmembrane proteins links the presynaptic and postsynaptic sides, with the intracellular C-terminal domains anchored to the first and second PDZ domains of Dlg. Hts is in a complex with Dlg at the postsynaptic membrane, though the interaction may not be direct. Hts also binds to PIP2 via the MARCKS-homology domain. (B) Hts promotes the accumulation of par-1 and camkII transcripts in the muscle cytoplasm through an as of yet identified mechanism. PAR-1 and CaMKII phosphorylate Dlg at serine 797 in the GUK domain and serine 48 in one of the PDZ domains respectively. Phosphorylation at either one of these sites disrupts Dlg postsynaptic targeting. (C) Phosphorylation of serine 704 in the MARCKS-homology domain translocates Hts away from the postsynaptic membrane and hinders Hts' ability to regulate Dlg localization, presumably through the control of PAR-1 and CaMKII at the transcriptional level. Phosphorylation of the MARCKS-homology domain also inhibits Hts' ability to bind to PIP2.

Mentions: Through the use of PLA, we show here that Hts forms complexes with Dlg and PIP2 at the postsynaptic region of the larval NMJ, with its ability to associate with these proteins being negatively regulated through phosphorylation of the MARCKS-homology domain (Fig. 8). Studies on mammalian adducin have demonstrated that phosphorylation of the MARCKS-homology domain impedes its actin-binding and spectrin-recruiting functions, reduces its affinity for these cytoskeletal components and the membrane, and targets it for proteolysis (Barkalow et al., 2003; Gilligan et al., 2002; Matsuoka et al., 1996; Matsuoka et al., 1998; Pariser et al., 2005). We propose that phosphorylation of the MARCKS-homology domain in the Add1/Add2 isoforms of Hts in response to upstream signaling events at the synapse reduces their affinity for spectrin-actin junctions and Dlg at the NMJ, but may also hinder their interactions with PIP2 and other phosphoinositides in line with the electrostatic switch model for phosphoinositide binding by the MARCKS-homology domain (Golebiewska et al., 2006; McLaughlin and Aderem, 1995).


Phospho-regulated Drosophila adducin is a determinant of synaptic plasticity in a complex with Dlg and PIP2 at the larval neuromuscular junction.

Wang SJ, Tsai A, Wang M, Yoo S, Kim HY, Yoo B, Chui V, Kisiel M, Stewart B, Parkhouse W, Harden N, Krieger C - Biol Open (2014)

Phosphorylation of the MARCKS-homology domain regulates Hts' interactions with Dlg and PIP2 at the postsynaptic membrane of larval NMJs.Schematic of a larval NMJ viewed in cross-section, with the presynaptic side shown at the top and the postsynaptic side shown at the bottom. (A) At the postsynaptic membrane, Dlg localizes to spectrin-actin complexes. Homophilic adhesion between Fasciclin 2 (Fas2) transmembrane proteins links the presynaptic and postsynaptic sides, with the intracellular C-terminal domains anchored to the first and second PDZ domains of Dlg. Hts is in a complex with Dlg at the postsynaptic membrane, though the interaction may not be direct. Hts also binds to PIP2 via the MARCKS-homology domain. (B) Hts promotes the accumulation of par-1 and camkII transcripts in the muscle cytoplasm through an as of yet identified mechanism. PAR-1 and CaMKII phosphorylate Dlg at serine 797 in the GUK domain and serine 48 in one of the PDZ domains respectively. Phosphorylation at either one of these sites disrupts Dlg postsynaptic targeting. (C) Phosphorylation of serine 704 in the MARCKS-homology domain translocates Hts away from the postsynaptic membrane and hinders Hts' ability to regulate Dlg localization, presumably through the control of PAR-1 and CaMKII at the transcriptional level. Phosphorylation of the MARCKS-homology domain also inhibits Hts' ability to bind to PIP2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265757&req=5

f08: Phosphorylation of the MARCKS-homology domain regulates Hts' interactions with Dlg and PIP2 at the postsynaptic membrane of larval NMJs.Schematic of a larval NMJ viewed in cross-section, with the presynaptic side shown at the top and the postsynaptic side shown at the bottom. (A) At the postsynaptic membrane, Dlg localizes to spectrin-actin complexes. Homophilic adhesion between Fasciclin 2 (Fas2) transmembrane proteins links the presynaptic and postsynaptic sides, with the intracellular C-terminal domains anchored to the first and second PDZ domains of Dlg. Hts is in a complex with Dlg at the postsynaptic membrane, though the interaction may not be direct. Hts also binds to PIP2 via the MARCKS-homology domain. (B) Hts promotes the accumulation of par-1 and camkII transcripts in the muscle cytoplasm through an as of yet identified mechanism. PAR-1 and CaMKII phosphorylate Dlg at serine 797 in the GUK domain and serine 48 in one of the PDZ domains respectively. Phosphorylation at either one of these sites disrupts Dlg postsynaptic targeting. (C) Phosphorylation of serine 704 in the MARCKS-homology domain translocates Hts away from the postsynaptic membrane and hinders Hts' ability to regulate Dlg localization, presumably through the control of PAR-1 and CaMKII at the transcriptional level. Phosphorylation of the MARCKS-homology domain also inhibits Hts' ability to bind to PIP2.
Mentions: Through the use of PLA, we show here that Hts forms complexes with Dlg and PIP2 at the postsynaptic region of the larval NMJ, with its ability to associate with these proteins being negatively regulated through phosphorylation of the MARCKS-homology domain (Fig. 8). Studies on mammalian adducin have demonstrated that phosphorylation of the MARCKS-homology domain impedes its actin-binding and spectrin-recruiting functions, reduces its affinity for these cytoskeletal components and the membrane, and targets it for proteolysis (Barkalow et al., 2003; Gilligan et al., 2002; Matsuoka et al., 1996; Matsuoka et al., 1998; Pariser et al., 2005). We propose that phosphorylation of the MARCKS-homology domain in the Add1/Add2 isoforms of Hts in response to upstream signaling events at the synapse reduces their affinity for spectrin-actin junctions and Dlg at the NMJ, but may also hinder their interactions with PIP2 and other phosphoinositides in line with the electrostatic switch model for phosphoinositide binding by the MARCKS-homology domain (Golebiewska et al., 2006; McLaughlin and Aderem, 1995).

Bottom Line: We provide evidence that Hts promotes the phosphorylation and delocalization of Dlg at the NMJ through regulation of the transcript distribution of the PAR-1 and CaMKII kinases in the muscle.We also show that Hts interactions with Dlg and PIP2 are impeded through phosphorylation of the MARCKS-homology domain.These results are further evidence that Hts is a signaling-responsive regulator of synaptic plasticity in Drosophila.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.

No MeSH data available.


Related in: MedlinePlus