title: Redox state influence on human galectin-1 function.
abstract: Intracellular and extracellular functions of human galectin-1 are influenced by its redox surroundings due to the presence of six cysteines within its amino acid sequence. Galectin-1 recognises intracellular-membrane-anchored Ras proteins that act as molecular switches regulating multiple signal transduction pathways. Human tumours frequently express Ras proteins that have become continuously activated due to point mutations, and this typically leads to deregulation of tumour cell growth, angiogenesis and invasion of metastatic cancer cells. Of significance is that galectin-1 preferably recognises H-Ras, one of the human Ras isoforms, and in particular galectin-1 recognition of the H-Ras farnesyl moiety is paramount to H-Ras membrane anchorage, a prerequisite step for H-Ras-mediated signal transduction regulating normal cell growth and malignant transformation. Herein the impact of the redox state on galectin-1's ability to interact with farnesyl analogues is explored. We demonstrate for the first time that reduced galectin-1 directly binds farnesyl and does so in a carbohydrate-independent manner. A K28T mutation abolishes farnesyl recognition by reduced dimeric galectin-1 whilst its carbohydrate-binding activity is retained, thus demonstrating the presence of an independent region on galectin-1 pertaining to growth inhibitory activity. Intriguingly, oxidised galectin-1 also recognises farnesyl, the biological implication of this novel finding is yet to be elucidated. Further, the redox effect on galectin-1 extracellular function was investigated and we discover that oxidised galectin-1 demonstrates a protective effect upon acute lymphoblastic leukaemia cells challenged by oxidative stress.
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Xing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Stacy A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: School of Medical Science, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Rhys
authors.initials: R
authors.lastname: Pritchard
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Houston
authors.affiliation: School of Medical Science, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia. Electronic address: h.blanchard@griffith.edu.au.
authors.forename: Helen
authors.initials: H
authors.lastname: Blanchard
mesh_terms: D002460:Cell Line; D037483:Galectin 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D010084:Oxidation-Reduction; D017354:Point Mutation / Q000235:genetics; D017433:Protein Structure, Secondary; D017382:Reactive Oxygen Species; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D037483:Galectin 1; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D018631:ras Proteins
keywords: Farnesyl; Galectin-1; Ras; Redox