High impact information on Sytl4

• Thus, granuphilin not only is essential for the docking of insulin granules but simultaneously imposes a fusion constraint on them through an interaction with the syntaxin-1a fusion machinery [1].
• The Rab27a effector granuphilin is specifically localized on insulin granules and is involved in their exocytosis [1].
• The enhanced secretion in mutant beta cells is correlated with a decrease in the formation of the fusion-incompetent syntaxin-1a-Munc18-1 complex, with which granuphilin normally interacts [1].
• Here we show that the number of insulin granules morphologically docked to the plasma membrane is markedly reduced in granuphilin-deficient beta cells [1].
• Granuphilin modulates the exocytosis of secretory granules through interaction with syntaxin 1a [2].

Biological context of Sytl4

• Surprisingly, despite the docking defect, the exocytosis of insulin granules in response to a physiological glucose stimulus is significantly augmented, which results in increased glucose tolerance in granuphilin-null mice [1].
• The domain structure of the protein products of the granuphilin gene contains an amino-terminal zinc-finger motif and carboxyl-terminal C(2)-domains, similar to that of the rabphilin-3 gene [3].
• The Slp1-3 C2 domains show high homology to granuphilin-a C2 domains, but the amino-terminal domain of Slp1-3 does not contain any known protein motifs or a transmembrane domain [4].
• Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor [5].

Anatomical context of Sytl4

• Thus, granuphilin is the first regulator in the exocytotic pathway that functions by directly connecting two critical vesicle transport proteins, Rab and SNARE [2].
• We have shown recently that Rab27a and its effector, granuphilin, are involved in the exocytosis of insulin-containing secretory granules through a direct interaction with the plasma membrane syntaxin 1a in pancreatic beta cells [6].
• A novel rabphilin-3-like gene, granuphilin, has been identified in pancreatic beta cells by comparing genes expressed in pancreatic alpha and beta cell lines using mRNA differential display [3].
• Slp4-a/granuphilin-a regulates dense-core vesicle exocytosis in PC12 cells [7].

Associations of Sytl4 with chemical compounds

• SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion [5].

Physical interactions of Sytl4

• Granuphilin directly binds to the H3 domain of syntaxin 1a containing its SNARE motif [6].
• Slp4-a/granuphilin-a interacts with syntaxin-2/3 in a Munc18-2-dependent manner [8].

Regulatory relationships of Sytl4

• Rab27 effector granuphilin promotes the plasma membrane targeting of insulin granules via interaction with syntaxin 1a [6].

Other interactions of Sytl4

• The peripheral location of granules is well overlapped with both localizations of granuphilin and syntaxin 1a [6].

References