The first close-up look at a pro-inflammatory signaling molecule involved in immune response in mammals suggests that researchers "should rethink what they are doing" in creating drugs based on a fruit-fly model, scientists say.
Reporting in the Oct. 1 issue of the Journal of Immunology, researchers at the University of Illinois at Urbana-Champaign unveiled the crystal structure of mouse interleukin-1 receptor-associated kinase-4 (IRAK-4).
They found a distinct highly structured loop between two helices that is remarkably different from that found in Pelle, an IRAK-4-like "death-domain" protein from Drosophila melanogaster that was determined nearly a decade ago. The death domain is so-named because of a resemblance to proteins that are involved in programmed cell death.
"It has been thought in the field that a death domain is a death domain, and molecular recognition takes place in the same fashion," said lead author Michael V. Lasker, an M.D./Ph.D. student in the College of Medicine at Urbana-Champaign. "But the crystal structure of our death domain clearly shows that indeed this is not the case."
The crystal structure of IRAK-4, as was the case for Pelle, was determined by X-ray crystallography. Using this technique, X-rays are directed into molecules of IRAK-4 that have been coaxed to form crystals. The diffraction data from the experiments allow the structure to be visualized down to angstrom-level resolution (one hundred-millionth of a centimeter). The structure of IRAK-4 was determined to a resolution of 1.7 angstroms.
The molecules in question are part of innate immune systems -- an inherent immune response coded by DNA in all living things -- that are crucial for survival against pathogens such as bacteria and fungi. Deficiencies in the system or an over-active response can set the stage for various infections, septic shock and numerous autoimmune disorders.
Since researchers at the University of Texas Southwestern in Dallas and the Howard Hughes Medical Institute reported the structure of Pelle bound to the adapter molecule known as Tube, there has been an effort to target the similar IRAK-4 molecule in mammals, said Satish K. Nair, a U. of I. professor of biochemistry.
The Pelle-Tube complex plays a crucial role in the innate immune response of fruit flies to fungal infection. IRAK-4 plays a similar role in humans and animals.