Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Structure. 2019 Apr 2;27(4):639-650.e2. doi: 10.1016/j.str.2019.01.009. Epub 2019 Feb 14.
KIR3DL1 is an inhibitory killer cell immunoglobulin-like receptor (KIR) that negatively regulates natural killer cell cytotoxicity. The KIR3DL1 cytoplasmic region (3DL1-cyto) is disordered and can be dissected into three segments: (I) H340-V351; (II) M352-D371; and (III) P372-P423. NMR studies indicate that segment II can dynamically adopt a loop-like conformation, and segments I and III can form dynamic helices that may mediate binding to membranes, particularly in the region around the N-terminal (N) immunoreceptor tyrosine-based inhibitory motif (ITIM), consistent with its role in signaling. Furthermore, individual SH2 domains of SHP-2 strongly engage with the unphosphorylated N-ITIM of 3DL1-cyto, while binding of the tandem SHP-2 SH2 domains to the bis-phosphorylated ITIMs results in more extensive conformational changes in segments I and III. The findings enhance our understanding of KIR function and how ITIMs in a target receptor operate in concert to engage the tandem SH2 domains of SHP-2.
KIR3DL1 是一种抑制性杀伤细胞免疫球蛋白样受体 (KIR)，可负向调节自然杀伤细胞的细胞毒性。KIR3DL1 的胞质区 (3DL1-cyto) 是无规则的，可以被分割成三个片段：(I) H340-V351；(II) M352-D371；和 (III) P372-P423。NMR 研究表明，片段 II 可以动态地采用环状构象，片段 I 和 III 可以形成动态螺旋，这可能介导与膜的结合，特别是在 N 端免疫受体酪氨酸基抑制基序 (ITIM) 的周围区域，与其信号转导作用一致。此外，SHP-2 的单个 SH2 结构域与 3DL1-cyto 的未磷酸化 N-ITIM 强烈结合，而串联 SHP-2 SH2 结构域与双磷酸化 ITIM 的结合导致片段 I 和 III 发生更广泛的构象变化。这些发现增进了我们对 KIR 功能的理解，以及靶受体中的 ITIM 如何协同作用以结合 SHP-2 的串联 SH2 结构域。
