Disease relevance of SYN1

• In order to investigate additional interactions of the synapsins with nerve terminal proteins, we have employed phage display library technology to select peptide sequences binding with high affinity to synapsin I [1].
• Previous studies identified synapsin I as a potential substrate for a newly discovered growth factor-sensitive, proline-directed protein kinase originally isolated from rat pheochromocytoma [2].
• Preincubation of botulinum neurotoxin serotype A, B, or E with ganglioside GT1b was previously found to enhance adherence of botulinum neurotoxin to synapsin I and an approximately 116-kDa bovine brain synaptosomal protein; in contrast, adherence to these two proteins by tetanus neurotoxin required preincubation with GT1b [3].
• Partial cleavage of synapsin I by collagenase, 2-nitro-5-thiocyanobenzoic acid, and Staphylococcus aureus V8 protease suggests that at least three glycosylation sites exist along the molecule [4].
• Cellular immune crossreactivity between myelin basic protein and synapsin in rats with experimental allergic encephalomyelitis [5].

High impact information on SYN1

• Synapsin or protein 4.1 in chromaffin cells [6].
• Synapsin I is thus a candidate to mediate or regulate the interaction of synaptic vesicles with microtubules [7].
• Synapsin I, a synaptic vesicle protein, is thought to be involved in the regulation of neurotransmission through its phosphorylation by the cyclic AMP-dependent and Ca2+/calmodulin-dependent protein kinases which become activated upon depolarization of nerve endings [7].
• We report here that synapsin I can co-cycle with microtubules through three cycles of warm polymerization and cold depolymerization [7].
• Synapsin I binds saturably to microtubules stabilized by taxol, with an estimated dissociation constant (Kd) of 4.5 microM and a stoichiometry of 1.2 mol of synapsin binding sites per mol tubulin dimer [7].

Biological context of SYN1

• The maximum stoichiometry of phosphorylation approached 1 mol of phosphate/mol of synapsin I protein [2].
• Although synapsin I has been implicated in synaptic transmission, no activity has been previously ascribed to it [8].
• In the present study, the interaction between synapsin I and phospholipid vesicles has been characterized, and the protein domains involved in these interactions have been identified [9].
• Synapsin I enhances both the rate and the extent of Ca(2+)-dependent membrane fusion, although it has no detectable fusogenic activity per se [10].
• The data indicate that synapsin I markedly affects synaptic vesicle traffic and cytoskeleton assembly in the nerve terminal and provide a molecular basis for the ability of synapsin I to regulate the availability of synaptic vesicles for exocytosis and thereby the efficiency of neurotransmitter release [11].

Anatomical context of SYN1

• The results indicate that an interaction between synapsin I and Rab3A exists on synaptic vesicles that modulates the functional properties of both proteins [12].
• However, despite its recent characterization as a spectrin-binding protein immunologically related to erythrocyte protein 4.1, other interactions of synapsin I with structural proteins remain unknown [7].
• These observations may explain why synapsin I is found exclusively in neurons, since small synaptic vesicles are specific to neurons whereas large dense-core vesicles in neurons may be considered the equivalent of secretory organelles in endocrine cells [13].
• No p38 was detectable on large dense-core vesicles (LDCVs). p38 and synapsin I were found to be present in similar concentrations throughout the brain [14].
• Synapsin I appears to bind G-actin with a very high stoichiometry (1:2-4), and the complex behaves as an F-actin nucleus, producing actin filaments under conditions where spontaneous polymerization is negligible [15].

Associations of SYN1 with chemical compounds

• Phosphorylation of synapsin I at a novel site by proline-directed protein kinase [2].
• Digestion of phosphorylated synapsin I with trypsin followed by high performance liquid chromatography (HPLC) phosphopeptide analysis indicated that the tryptic peptide containing the major phosphorylation site eluted as a single peak at approximately 17% acetonitrile [2].
• We further show that brain 4.1 is identical to the synaptic vesicle protein, synapsin I, one of the brain's major substrates for cyclic AMP and Ca2+-calmodulin-dependent kinases [8].
• Characterization of synapsin I fragments produced by cysteine-specific cleavage: a study of their interactions with F-actin [16].
• Synapsin I is composed of two distinct domains, a COOH terminal, collagenase-sensitive, hydrophilic, and strongly basic tail region, and an NH2 terminal, collagenase-resistant head region relatively rich in hydrophobic amino acids [16].

Physical interactions of SYN1

• ACAMP-81 bound to the cysteine specific cleaved 51 kDa fragment derived from middle/tail region of synapsin I [17].

Other interactions of SYN1

• We report partial amino acid analysis of ACAMP-81 and its interaction with synapsin I [17].
• The kcat values were: G-substrate, 0.41 s-1; DARPP-32, 0.20 s-1; Protein K.-F., 0.7 s-1; synapsin I (site I), 0.053 s-1; synapsin I (site II), 0.040 s-1 [18].
• The beta-elimination of galactosyltransferase radiolabeled synapsin I and subsequent analysis of released saccharide on high-voltage paper electrophoresis confirmed the presence of monosaccharidic GlcNAc moieties in O-linkage to the protein [4].
• Similar behavior is observed when synapsin replaces MBP, while acetylated MBP and bovine serum albumin fail to induce any fluorescence change [19].
• The kinase preparation was also able to phosphorylate exogenous synapsin, phospholamban, glycogen synthase, MAP-2, myelin basic proteins and kappa-casein, but not tubulin, pyruvate kinase, the regulatory subunit of cAMP protein kinase II, myosin light chain or phosphorylase b [20].

Analytical, diagnostic and therapeutic context of SYN1

• Mixtures of synapsin I and tubulin observed by negative stain electron microscopy contain bundles of microtubules, accounting for the effect of synapsin I on tubulin turbidity [7].
• Immunocytochemistry revealed that synapsin I is preferentially (and possibly exclusively) associated with small (40- to 60-nanometer) synaptic vesicles and not with large (greater than 60-nanometer) dense-core vesicles in bovine hypothalamus [13].
• Dephosphorylated synapsin I anchors synaptic vesicles to actin cytoskeleton: an analysis by videomicroscopy [11].
• This interpretation was also supported by circular dichroism spectra of synapsin I, which showed induction of secondary structure in the presence of trifluoroethanol [21].
• In addition, two-dimensional peptide-mapping analysis revealed some homology between major phosphopeptide fragments of Synapsin I and the fish proteins [22].

References