Kristensen Ole, Guenat Sylvie, Dar Imran, Allaman-Pillet Nathalie, Abderrahmani Amar, Ferdaoussi Mourad, Roduit Raphaël, Maurer Fabienne, Beckmann Jacques S, Kastrup Jette S, Gajhede Michael, Bonny Christophe
Biostructural Research, Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
EMBO J. 2006 Feb 22;25(4):785-97. doi: 10.1038/sj.emboj.7600982. Epub 2006 Feb 2.
Islet-brain 1 (IB1 or JIP-1) is a scaffold protein that interacts with components of the c-Jun N-terminal kinase (JNK) signal-transduction pathway. IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components and secretion. IB1 has been shown to homodimerize, but neither the molecular mechanisms nor the function of dimerization have yet been characterized. Here, we show that IB1 homodimerizes through a novel and unique set of Src homology 3 (SH3)-SH3 interactions. X-ray crystallography studies show that the dimer interface covers a region usually engaged in PxxP-mediated ligand recognition, even though the IB1 SH3 domain lacks this motif. The highly stable IB1 homodimer can be significantly destabilized in vitro by three individual point mutations directed against key residues involved in dimerization. Each mutation reduces IB1-dependent basal JNK activity in 293T cells. Impaired dimerization also results in a reduction in glucose transporter type 2 expression and in glucose-dependent insulin secretion in pancreatic beta-cells. Taken together, these results indicate that IB1 homodimerization through its SH3 domain has pleiotropic effects including regulation of the insulin secretion process.
胰岛脑1（IB1或JIP-1）是一种支架蛋白，它与c-Jun氨基末端激酶（JNK）信号转导途径的组分相互作用。IB1在神经元和胰岛β细胞中高水平表达，在这些细胞中它控制几种胰岛素分泌组分的表达和分泌。已有研究表明IB1能形成同源二聚体，但二聚化的分子机制和功能尚未得到阐明。在此，我们表明IB1通过一组新颖独特的Src同源结构域3（SH3）-SH3相互作用形成同源二聚体。X射线晶体学研究表明，二聚体界面覆盖了通常参与PxxP介导的配体识别的区域，尽管IB1的SH3结构域缺乏该基序。高度稳定的IB1同源二聚体在体外可被针对二聚化关键残基的三个单点突变显著破坏稳定性。每个突变都会降低293T细胞中依赖IB1的基础JNK活性。二聚化受损还会导致胰岛β细胞中2型葡萄糖转运蛋白表达减少以及葡萄糖依赖性胰岛素分泌减少。综上所述，这些结果表明，IB1通过其SH3结构域形成同源二聚体具有多效性作用，包括调节胰岛素分泌过程。
