Structure-function studies on recombinant human macrophage colony-stimulating factor (M-CSF).
Year: 1994
Type: article
Abstract: Human macrophage colony-stimulating factor (M-CSF) is a homodimeric cytokine that is a member of a structurally related family of hormones defined by an unusual up-up-down-down alpha-helical bundle. To identify regions on the surface of M-CSF that might interact with the M-CSF receptor, single and double amino acid substitutions were introduced into a truncated form of human M-CSF alpha by site-directed mutagenesis, and the homodimeric M-CSF analogs were purified and characterized. Certain substitutions in the region before and in helix A and in helix C decreased specific bioactivity and correlated with an approximately equivalent reduction in M-CSF receptor affinity. The most dramatic change was observed in an analog in which residues His-9 and His-15 were replaced with alanines, resulting in a 9,100-fold decrease in specific bioactivity. X-ray crystallographic analysis of this M-CSF alpha H9A,H15A analog at a resolution of 2.5 A revealed no significant changes in structure other than the expected new side chains at residues 9 and 15. Analogs containing only one of these two histidine substitutions exhibited a decrease in specific bioactivity of 6- and 1200-fold for the H9A and H15A mutations, respectively. It appears that selected amino acids in the NH2-terminal region of M-CSF and possibly portions of the surface formed by helices A and C are significantly involved in interactions with the M-CSF receptor.
Source: Journal of Biological Chemistry
Authors: E W Taylor, A L Fear, A Bohm, S H Kim, K Koths
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1543489149