Investigation into Human Galectin-1 Structure and Function

Abstract

Human galectin-1 is a lectin protein that is ubiquitously expressed by most normal adult tissues, and is also over-expressed by many human cancers. When in a reducing environment, human galectin-1 exhibits specific binding affinity for [beta]-galactosides and exists in a non-covalently bound homodimer conformation comprised of two 14.5 kDa subunits. Dimeric human galectin-1 exhibits cross-linking lectin activity because one carbohydrate-binding site per subunit is located at each end of the dimer. Mediated by cross-linking lectin activity, extracellular human galectin-1 is able to cluster specific glycoconjugate receptors on the T cell surface to initiate apoptosis. The apoptotic affects of extracellular galectin-1 upon T cells suggests that secretion of galectin-1 into the tumour stroma indirectly contributes to tumour survival and growth by essentially creating a "shield" from immune surveillance. Human galectin-1 cross-linking lectin activity also promotes cell migration and adhesion, two critical processes in angiogenesis and the invasion of metastatic cancer cells. Consequently, the production of [beta]-galactoside derivatives as a means of specific inhibition of galectin-1 has become a focus in today's fight against cancer. For human galectin-1 to maintain cross-linking lectin activity, six cysteine residues within each subunit of the homodimer must be kept from oxidizing to form inter- and/or intramolecular disulphide bonds. Considering most cancers are associated with oxidative stress, it is intriguing to contemplate whether an oxidized form of human galectin-1 functions within a cancerous environment. An oxidized monomeric form of human galectin-1 (14.5 kDa) is known to interact with the cell surface of macrophages and stimulate their release of an axonal regeneration factor(s), however, the role oxidized human galectin-1 may play in tumourigenesis is currently unsubstantiated. Attempts to generate the oxidized monomeric form for further study during this Ph.D resulted in the generation of two forms of oxidized human galectin-1, an oligomer 68 kDa in size and a smaller protein species of apparent molecular weight 17 kDa. [...]