Position: Professor of Basic Biomedical Science, Wellcome Trust Senior Fellow and Associate Dean of Postgraduate Matters
Division: Cell Signalling and Immunology
Address: College of Life Sciences,
University of Dundee,
Dundee
Telephone: +44 1382 385781, int ext. 85781
Fax: +44 1382 385783
Email: p.r.crocker@dundee.ac.uk
Website: Paul Crocker Lab Website
A key feature of the innate immune system is the ability to recognise and react to foreign invaders. An inherent risk of this process is that inappropriate reactivity against host tissues can result in tissue damage and autoimmune diseases. Recent evidence suggests that certain determinants present on host cells, which are absent from pathogens, can interact with 'inhibitory receptors' on the host leucocytes and damp down autoreactivity. The research in our laboratory is focussed on structure-function relationships for a newly-described family of receptors of the immunoglobulin superfamily called siglecs (figure 1a). These proteins recognise a family of carbohydrates called sialic acids which are abundantly expressed on host cell surfaces. Many of the eleven known human siglec receptors are expressed in a highly specific manner on different leucocyte subsets (figure 1c) and have molecular features of inhibitory receptors, including conserved tyrosine-based motifs. By recruiting cytosolic phosphatases and other signalling molecules, inhibitory receptors modulate activation of leucocytes and may help prevent autoreactivity. We are currently studying how sialic acid recognition by siglec receptors regulates leucocyte activation using a variety of in vitro and in vivo experimental systems. These include x-ray crystallography in collaboration with Daan van Aalten as well as biochemical and genetic approaches.
(a) Diagram of all known human siglecs. Coloured circles in the cytoplasmic tails represent potential tyrosine-based signaling motifs that are well-conserved amongst all human CD33-related siglecs.
(b) Positions of key residues in the N-terminal V set domain of sialoadhesin that contact sialic acid (black). This template for sugar recognition is believed to be conserved in all siglecs.
(c) Diagram illustrating expression of siglecs in the human immune system
For further information, see Crocker and Varki (2001) Trends in Immunology 22, 337.
1. Heikema AP, Bergman MP, Richards H, Crocker PR, Gilbert M, Samsom JN, van Wamel WJ, Endtz HP, van Belkum A: Characterization of the specific interaction between sialoadhesin (Siglec-1) and sialylated Campylobacter jejuni lipooligosaccharides. Infection and immunity 2010 E-pub ahead of print
6. Ducreux J, Vanbever R, Crocker PR: The inhibitory potencies of monoclonal antibodies to the macrophage adhesion molecule sialoadhesin are greatly increased following PEGylation. Bioconjugate chemistry 2008, 19(10):2088-2094.
7. McMillan SJ, Crocker PR: CD33-related sialic-acid-binding immunoglobulin-like lectins in health and disease. Carbohydrate research 2008, 343(12):2050-2056
