08:11am Monday 18 November 2019

Understanding a molecule that helps, but can harm

• It’s a garbage truck on patrol, sweeping up and removing dead and damaged cells, other debris, and fat
• It’s a search-and-destroy weapon, coursing through our bloodstream to disarm enemy aliens such as the parasite that causes malaria
• It’s a key gate-keeper sitting on the cell surface, modulating the energy-fuel pipeline into the cell

Thus, the multitalented molecule CD36 participates in molecular recognition, in signaling, and in the delivery of nutrients into cells. This extraordinary range of roles suggests that CD36 acts with other molecules to mediate the function of healthy cells and to promote the body’s ability to control infection.  

Using a combination of imaging, biochemical, and genetic tools, SickKids researchers Dr. Sergio Grinstein and Dr. William Trimble and their team present a detailed structural and functional analysis of this critical structure online in Developmental Cell, February 7, 2013.

CD36 identifies things that pose a danger – such as malaria-infected red blood cells and bad cholesterol associated with modified LDL – removing them from the circulation or from affected tissues. In this role, CD36 both helps and harms. “When macrophages use CD36 to engulf threatening bodies, such as oxidized LDL, they can swell and become foamy, becoming paralyzed under the lining of blood vessels.  The resulting plaque can break off and cause a stroke or heart attack,” Dr. Grinstein says.  He is a Senior Scientist of Cell Biology at SickKids and Professor of Biochemistry at University of Toronto.

CD36 image

In addition, he points out that attachment of malaria-infected red cells to CD36 molecules on the wall of blood vessels can plug capillaries in the brain, causing death.

Impact: The implications of this work reach across malaria, atherosclerosis and cardiovascular disease, and beyond. “Full understanding of how CD36 works extends the potential for new therapeutic approaches to preventing and treating these diseases,” says Dr. Grinstein.  

Summary:  CD36 forms complexes with β1 and β2 integrins and the tetraspanins CD9/CD81. These complexes engage immunoreceptor tyrosine activation motif (ITAM) adaptor FcRλ. FcRλ links CD36 complexes to Src-family kinases, SyK, and endocytosis. These interactions control internalization of CD36 ligands such as oxidized LDL.

The research is titled, “Multimolecular signaling complexes enable Syk-mediated signaling of CD36 internalization,” Developmental Cell, published online February 7, 2013. Co-authors are Drs. William Trimble, Sergio Grinstein, Bryan Heit, Gabriela Cosío, Diana Castaño, and Richard Collins of SickKids, as well as Hani Kim, Clifford Lowell, and Kevin C. Kain.

Funders include SickKids Foundation, Canadian Institutes of Health Research, Heart & Stroke Foundation, and the Pitblado Chair in Cell Biology.

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