Structural highlights
Function
[SIGL7_HUMAN] Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- and alpha-2,6-linked sialic acid. Also binds disialogangliosides (disialogalactosyl globoside, disialyl lactotetraosylceramide and disialyl GalNAc lactotetraoslylceramide). The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface. In the immune response, may act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Mediates inhibition of natural killer cells cytotoxicity. May play a role in hemopoiesis. Inhibits differentiation of CD34+ cell precursors towards myelomonocytic cell lineage and proliferation of leukemic myeloid cells (in vitro).[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Siglecs (sialic acid binding Ig-like lectins) are transmembrane receptors for sialylated glycoconjugates that modulate cellular interactions and signalling events in the haematopoietic, immune and nervous systems. Siglec-7 is a structural prototype for the recently described family of immune inhibitory CD33-related siglecs and is predominantly expressed on natural killer cells and monocytes, as well as subsets of CD8 T-cells. Siglec-specific inhibitors are desired for the detection of masked and unmasked forms of siglecs, to aid in dissection of signalling pathways and as tools to investigate siglecs as potential therapeutic targets. As a first step towards this end, we present the crystal structure of siglec-7 in complex with a sialylated ligand, the ganglioside analogue DSLc4 [alpha(2,3)/alpha(2,6) disialyl lactotetraosyl 2-(trimethylsilyl)ethyl], which allows for a detailed description of the binding site, required for structure-guided inhibitor design. Mutagenesis and binding assays were used to demonstrate a key structural role for Lys131, a residue that changes conformation upon sialic acid binding. Differences between the binding sites of siglec family members were then exploited using alpha-methyl Neu5Ac (N-acetylneuraminic acid) as a basic scaffold. A co-crystal of siglec-7 in complex with the sialoside inhibitor, oxamido-Neu5Ac [methyl alpha-9-(amino-oxalyl-amino)-9-deoxy-Neu5Ac] and inhibition data for the sialosides gives clear leads for future inhibitor design.
The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design.,Attrill H, Takazawa H, Witt S, Kelm S, Isecke R, Brossmer R, Ando T, Ishida H, Kiso M, Crocker PR, van Aalten DM Biochem J. 2006 Jul 15;397(2):271-8. PMID:16623661[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Vitale C, Romagnani C, Falco M, Ponte M, Vitale M, Moretta A, Bacigalupo A, Moretta L, Mingari MC. Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15091-6. PMID:10611343
- ↑ Attrill H, Takazawa H, Witt S, Kelm S, Isecke R, Brossmer R, Ando T, Ishida H, Kiso M, Crocker PR, van Aalten DM. The structure of siglec-7 in complex with sialosides: leads for rational structure-based inhibitor design. Biochem J. 2006 Jul 15;397(2):271-8. PMID:16623661 doi:http://dx.doi.org/10.1042/BJ20060103
