Disease relevance of Synj1

• The central region of synaptojanin defines it as a member of the inositol-5-phosphatase family, which includes the product of the gene that is defective in the oculocerebrorenal syndrome of Lowe [1].
• We have used synaptojanin purified from Sf9 cells after baculovirus mediated expression in overlay assays to identify two major synaptojanin-binding proteins in rat brain [2].

High impact information on Synj1

• Synaptojanin is the only other major brain protein besides dynamin that binds the SH3 domain of amphiphysin, a presynaptic protein with a putative function in endocytosis [1].
• Synaptojanin is a nerve terminal protein of relative molecular mass 145,000 which appears to participate with dynamin in synaptic vesicle recycling [1].
• The carboxy terminus, which is of different lengths in adult and developing neurons owing to the alternative use of two termination sites, is proline-rich, consistent with the reported interaction of synaptojanin with the SH3 domains of Grb2 (refs 1, 2) [1].
• Synaptojanin 1 and PIPKIgamma antagonize each other in the recruitment of clathrin coats to lipid membranes [3].
• Our findings provide evidence that OMP25 mediates recruitment of synaptojanin 2A to mitochondria and that modulation of inositol phospholipids by synaptojanin 2A may play a role in maintenance of the intracellular distribution of mitochondria [4].

Biological context of Synj1

• Our results demonstrate the presence of a family of synaptojanin-type inositol 5'-phosphatases with different tissue and subcellular distributions, which may be involved in distinct membrane trafficking and signal transduction pathways in mammalian cells [5].
• We have now identified and characterized a novel form of synaptojanin, synaptojanin 2, which has a broader tissue distribution [5].
• Endophilin 1 is proposed to participate in synaptic vesicle biogenesis through SH3 domain-mediated interactions with the polyphosphoinositide phosphatase synaptojanin and the GTPase dynamin [6].
• Tissue-specific alternative splicing generates two synaptojanin isoforms with differential membrane binding properties [7].
• Amphiphysin I is an abundant presynaptic protein that interacts via its COOH-terminal src homology 3 (SH3) domain with the GTPase dynamin I and the inositol-5-phosphatase synaptojanin [8].

Anatomical context of Synj1

• Synaptojanin (synaptojanin 1) is a recently identified inositol 5'-phosphatase, which is highly enriched in nerve terminals and is implicated in synaptic vesicle recycling [5].
• The 40-kDa synaptojanin-binding protein was partially purified from rat brain cytosol through a three-step procedure involving ammonium sulfate precipitation, sucrose density gradient centrifugation, and DEAE ion-exchange chromatography [2].
• Both dynamin I and synaptojanin I have a putative role in synaptic vesicle recycling and undergo rapid dephosphorylation in rat brain synaptosomes stimulated to secrete by a depolarizing stimulus [8].
• Intraneuronal trafficking and distribution of amphiphysin and synaptojanin in the rat peripheral nervous system and the spinal cord [9].
• Immuno-EM showed that both amphiphysin and synaptojanin are primarily associated with heterogeneous membrane profiles in the crushed sciatic nerve and the immunoperoxidase reaction product is concentrated in the nerve terminal cytomatrix of the spinal cord [9].

Associations of Synj1 with chemical compounds

• At least two of the ArgBP2/nArgBP2 binding partners, synaptojanin 2B and WAVE2, undergo ubiquitination and Abl-dependent tyrosine phosphorylation [10].
• Further characterization of the enzymatic properties of synaptojanin now shows that it hydrolyzes only the 5-phosphate from inositol 1,4,5-trisphosphate (I(1,4,5)P3) and that it does not catalyze the dephosphorylation of either I(1,3,4)P3 or inositol 1, 4-bisphosphate [11].
• Synaptojanin inhibition of phospholipase D activity by hydrolysis of phosphatidylinositol 4,5-bisphosphate [11].
• Synaptojanin is the major constitutively active phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase in rodent brain [12].
• However, synaptojanin hydrolyzes both the 4- and 5-phosphates of PI(4,5)P2 and the 4-phosphate of phosphatidylinositol 4-phosphate, converting both compounds to phosphatidylinositol [11].

Physical interactions of Synj1

• Further experimental results suggested that rtSH3p13 forms a complex with activated epidermal growth factor receptor (EGFR) and interacts with synaptojanin I [13].

Other interactions of Synj1

• We have used the proline-rich tail of synaptojanin to screen a rat brain library by the two-hybrid method to identify additional interacting partners of synaptojanin [14].
• Dynamin I and at least five other nerve terminal proteins, amphiphysins I and II, synaptojanin, epsin and eps15 (collectively called dephosphins), are coordinately dephosphorylated by calcineurin during endocytosis of synaptic vesicles [15].
• CFS analysis demonstrated that only 30% of fast anterogradely transported amphiphysin and synaptojanin was returned by fast retrograde transport, in contrast to the 70% value observed for synaptophysin, a transmembrane protein [9].
• This enzyme hydrolyzed phosphate at the D-5 position of inositol 1,4,5-trisphosphate, inositol 1,3,4, 5-tetrakisphosphate, and phosphatidylinositol 4,5-bisphosphate, consistent with the substrate specificity of type II 5-phosphatase, OCRL, synaptojanin and synaptojanin 2, already characterized 5-phosphatases [16].
• Interaction of phospholipase C gamma 1 via its COOH-terminal SRC homology 2 domain with synaptojanin [17].

Analytical, diagnostic and therapeutic context of Synj1

• Using crystallography, we show that FxDxF and WVxF peptide motifs from synaptojanin bind to distinct subdomains on alpha-appendages, called 'top' and 'side' sites [18].
• Immunoprecipitation from crude lysates of rat brain tissue showed that synaptojanin accounts for the major part of the active PtdIns(3, 4,5)P3 5-phosphatase activity [12].
• Since synaptojanin is not known to possess PtdIns(3,4,5)P3 5-phosphatase activity, we verified that the purified PtdIns(3,4,5)P3 5-phosphatase activity and synaptojanin are identical by Western blot using specific antibodies raised against synaptojanin sequences [12].
• The localization of mRNAs for synaptojanin 1 and 2, inositol 5-phosphatases, in the brain was examined by in situ hybridization histochemistry [19].

References