Kurt Drickamer

Current Institution
Imperial College, London
Wellcome Principal Research Fellow
Glycobiology Institute

Scholar: 1982

Awarded Institution
The University of Chicago


Research Interests

Complex carbohydrates are found at the cell surface, attached to lipids and proteins in the membrane, and on secreted glycopreteins that reside in extracellular matrices and in biological fluids such as serum. Information encoded in the diverse carbohydrate structures of glycoproteins and glycolipids can be decoded by animal lectins (sugar-binding proteins). Although these lectins are structurally and functionally diverse, a significant number of them are calcium-dependent. In many cases, the saccharide-binding activity of this group of lectins can be ascribed to discrete calcium-dependent carbohydrate-recognition domains (C-type CRDs). Animal lectins containing such CRDs serve their biological functions by recognizing either endogenous or exogenous carbohydrate structures.

Recognition of endogenous glycoconjugates by membrane-bound C-type animal lectins is involved in sorting of glycoproteins and in cell adhesion. The sorting function is exemplified by the asialoglycoprotein receptor of mammalian liver, which mediates clearance of diverse glycoproteins from the circulation triggered by removal of terminal sialic acid residues from complex N-linked oligosaccharides. The best studied example of carbohydrate-based cell adhesion is the initiation of extravasation resulting from binding of moving leukocytes to endothelial cells, which is mediated by selectin cell adhesion molecules. Each selectin contains an amino-terminal C-type CRD, while many lectins that mediate clearance, such as the asiloglycoprotein receptor, have COOH-terminal CRDs.

Lectins that recognize exogenous ligands include the macrophage mannose receptor, a membrane recptor with multiple C-type CRDs, and the collectins, which contain CRDs linked to amino-terminal collagen-like tails. These proteins mediate an innate immune response, based on the fact that the surfaces of many potentially pathogenic organisms are rich in mannose and nitrogen-acetylglycosamine, while these such sugars are much less often displayed in an exposed form on mammalian cells. The soluble collectins mediate complement fixation and opsonization while binding to the macrophage receptor leads directly to phagocytosis. The importance of this relatively crude type of self versus nonself discrimination has been emphasized by the finding that children deficient in one collectin, mannose-binding protein, are subject to recurrent, severe infection during the period when maternal immunity is waning but their own antibody repertoire is not fully developed.

As a first step toward understanding C-type CRDs at the molecular level, the structure of the CRD from rat serum mannose-binding protein was deduced in collaboration with Dr. William Weis. We are utilizing this and related structural information as a basis for developing a detailed molecular description of how idividual CRDs interact with monosaccharides. Since C-type CRDs share an underlying sequence motif, they are probably folded in similar ways. Although each binds to a unique spectrum of sugars, the mechanism for sugar recognition by all of these domains is likely to be related. A principal goal is to define, at the primary and tertiary structure levels, why certain C-type CRDs bind to galactose and related sugars while others show specificity for mannose and related sugars. A further goal is to determine how certain CRDs bind more selectively to amino sugar derivatives and how those in the selectins bind to complex structures such as the sialyl Lewis-x tetrasaccharide.

In order to understand how intact lectin molecules interact with multivalent oligosaccharides, we would like to define the arrangement of multiple CRDs within animal lectins. Clustering of C-type CRDs is often brought about by oligomerization of identical or nonidentical polypeptides each containing a single CRD. The goals in this portion of the program are to understand what holds the oligomers together and to define geometrical relationships between CRDs needed for binding to complex ligands.

For those lectins that mediate endocytosis, release of ligands in endosomes folowing endocytosis allows segregation of the bound ligand which can be routed to lysosomes for degradation while the receptor recycyles to the plasma membrane. It is our aim to determine what changes in CRDs are responsible for this loss of ligand-binding activity. We know that the decrease in affinity for sugar results from loss of calcium-binding activity, which is mediated by several loops in the polypeptide. Our specific goal is to determine what portions of the CRD change conformation and to identify amino acid side chains that become protonated at endosomal pH.

Isolated, expressed CRDs can also be used as tools to probe for high affinity endogenous ligands. For example, an immobilized form of a CRD found at the COOH terminus of a proteoglycan core protein derived from extracellular matrix is being used to screen for endogenous ligands that will be isolated and characterized. In this way, the study of CRD-sugar interaction is being expanded to analysis of function in a biological context.