Conformational Changes in the Cytoplasmic Region of KIR3DL1 upon Interaction with SHP-2

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.