Structure-based site-directed photo-crosslinking analyses of multimeric cell-adhesive interactions of voltage-gated sodium channel β subunits.
Structure-based site-directed photo-crosslinking analyses of multimeric cell-adhesive interactions of voltage-gated sodium channel β subunits.
复制标题
DOI：
10.1038/srep26618
复制
发表时间：
2016-05-24
影响因子：
4.6
通讯作者：
Yokoyama S
中科院分区：
文献类型：
--
作者：
Shimizu H;Miyazaki H;Ohsawa N;Shoji S;Ishizuka-Katsura Y;Tosaki A;Oyama F;Terada T;Sakamoto K;Shirouzu M;Sekine S;Nukina N;Yokoyama S
据报道，电压门控钠通道的β1、β2和β4亚单位具有细胞黏附分子的功能。目前对β4胞外域的结晶学分析表明，β4分子在晶格中呈反平行排列。两个反平行的β4分子之间的界面是不对称的，并导致多聚体组装。β-4介导的细胞-细胞黏附的结构诱变和定点光交联分析表明，在细胞-细胞黏附中，反平行的β-4分子之间的界面对应于β-4多聚体组装的反式亲和性相互作用。这种反式相互作用模式也被用于β-1介导的细胞-细胞黏附。此外，β-1基因突变与全身性癫痫伴热性惊厥发作(GEFS+)相关，损害了β-1介导的细胞-细胞黏附，这可能是GEFS+发病机制的基础。从而为β亚单位介导的细胞-细胞黏附奠定了结构基础。
The β1, β2, and β4 subunits of voltage-gated sodium channels reportedly function as cell adhesion molecules. The present crystallographic analysis of the β4 extracellular domain revealed an antiparallel arrangement of the β4 molecules in the crystal lattice. The interface between the two antiparallel β4 molecules is asymmetric, and results in a multimeric assembly. Structure-based mutagenesis and site-directed photo-crosslinking analyses of the β4-mediated cell-cell adhesion revealed that the interface between the antiparallel β4 molecules corresponds to that in the trans homophilic interaction for the multimeric assembly of β4 in cell-cell adhesion. This trans interaction mode is also employed in the β1-mediated cell-cell adhesion. Moreover, the β1 gene mutations associated with generalized epilepsy with febrile seizures plus (GEFS+) impaired the β1-mediated cell-cell adhesion, which should underlie the GEFS+ pathogenesis. Thus, the structural basis for the β-subunit-mediated cell-cell adhesion has been established.