TITLE

Crystal structure of LIR-2 (ILT4) at 1.8 Ã…: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18

AUTHOR(S)
Willcox, Benjamin E.; Thomas, Leonard M.; Chapman, Tara L.; Heikema, Astrid P.; West Jr., Anthony P.; Bjorkman, Pamela J.
PUB. DATE
January 2002
SOURCE
BMC Structural Biology;2002, Vol. 2, p6
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Leukocyte Immunoglobulin-like Receptor-1 (LIR-1) and LIR-2 (also known as ILT2 and ILT4 respectively) are highly related cell surface receptors that bind a broad range of class I MHC molecules with low (µM) affinities. Expressed on monocytic cells and macrophages, both molecules transmit inhibitory signals after binding ligands. In addition to binding host class I MHC, the LIR-1 molecule, which is also expressed on lymphoid tissues, binds with a high (nM) affinity to UL18, a class I MHC homolog encoded by Human Cytomegalovirus (HCMV). In comparison, LIR-2 binds UL18 only weakly (µM KD). To understand how HCMV preferentially targets the more broadly expressed LIR-1 molecule, we determined the crystal structure of a ligand-binding fragment of LIR-2, and compared this to the existing high-resolution crystal structure of LIR-1. Results: Recombinant LIR-2 (domains 1 and 2) was produced in E. coli and crystallized using streak seeding to optimize the crystal morphology. A data set complete to 1.8 Å was collected at 100 K from a single crystal in the P41212 spacegroup. The structure was solved by molecular replacement, using a search model based on the LIR-1 structure. Conclusions: The overall structure of LIR-2 D1D2 resembles both LIR-1, and Killer Inhibitory Receptors, in that the A strand in each domain forms hydrogen bonds to both β sheets, and there is a sharp angle between the two immunoglobulin-like domains. However, differences from LIR-1 are observed in each domain, with two key changes apparent in the ligand-binding domain, D1. The region corresponding to the residue 44-57 helix of LIR-1 adopts a topology distinct from that of both LIR-1 and the KIR structures, involving a shortened 310 helix. Secondly, the predicted UL18 binding region of LIR-1 is altered substantially in LIR-2: the 76-84 loop mainchain is displaced 11 Å with respect to LIR-1, and Tyrosine 38 adopts an alternative rotamer conformation. In summary, the structure of LIR-2 has revealed significant differences to LIR-1, including ones that may help to explain the >1000-fold lower affinity of LIR-2 for UL18.
ACCESSION #
29323532

 

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