Protein Binding

Edited by: Thomas W. Durso S.D. Rosen, C.R. Bertozzi, "The selectins and their ligands," Current Opinion in Cell Biology, 6:663-73, 1994. (Cited in more than 60 publications through April 1996) Comments by Steven D. Rosen, University of California, San Francisco The selectins are a trio of related proteins involved in leukocyte-endothelium interactions, affecting the ability of leukocytes-that is, white blood cells-to interact with blood vessel walls. THREEPEAT: The selectins are a threesome of related proteins, says UC-San Francisco's Steven Rosen. First identified at the molecular level in 1989 (L.M. Stoolman, Cell, 56:907-10, 1989), selectins are the topic of this review paper by Steven D. Rosen, a professor in the department of anatomy and program in immunology at the University of California, San Francisco, and Carolyn R. Bertozzi, a former postdoc in Rosen's lab and now an assistant professor of chemistry at the University of California, Berkeley. The paper summarizes the three selectins and their physiological functions in leukocyte-endothelium interactions, and describes how they function. "One of the novel aspects of the selectins is that they function as carbohydrate-binding receptor molecules-that is, they recognize specific carbohydrate structures as their ligands, or counter-receptors," Rosen says. "This means that in principle, it's possible to interrupt the function of selectins by determining what carbohydrates they bind to and providing mimics for those carbohydrates in the form of soluble small molecules, thereby arriving at a new class or classes of anti-inflammatory substances." Rosen explains that with leukocytes moving from the blood into tissues, the leukocyte-endothelium interaction is critical to inflammatory reactions. ONE PLACE: UC-Berkeley's Carolyn Bertozzi, Rosen's former postdoc, was coauthor of the review paper. "In many cases, inflammatory reactions lead to pathological problems," he points out. "It's a defense mechanism the body has, but leukocytes being in tissue sites can cause problems as well as be of value to the individual. "Leukocytes in tissue sites are protecting the individual from bacterial invasions and foreign substances that the individual wants to eliminate, but leukocytes can have an arsenal of destructive capabilities which can be turned on the individual's own tissues. So inflammatory reactions have a down side. There are a lot of inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, lupus, and other autoimmune diseases." He concludes: "The interest in the selectins was: Here's a family of proteins that has involvement in leukocyte-endothelium interactions, therefore here's a potential set of targets to prevent leukocyte entry into tissues and prevent inflammatory problems." Asked for his opinion on why this paper has been cited so much, Rosen replies: "There's a huge amount of interest in the selectins, because there's basic cell biology and biochemistry that everybody's interested in here. . . . There's a real convergence of the basic science with direct clinical applications. What you do in the lab can have immediate ramifications on the design of anti-inflammatory compounds. There's tremendous biotech and pharmaceutical company interest in the selectins and their ligands. "This has been a tremendously hot topic since 1989, and it will be for years to come. Our article put everything down in one place, from the basic cell biology to the clinical connections, and updated the carbohydrate information and ligand identification information in a very accessible way." In addition to reviewing the selectins, Rosen states, "the paper deals with what is known about the carbohydrates that the selectins recognize, and what is known about the macromolecules-the ligands-that carry these carbohydrates. What might make the carbohydrates that one selectin recognizes different from the carbohydrates that another selectin molecule might recognize-that is, what is the selectivity of carbohydrate binding among the three selectins?" The paper also lists the animal models of inflammatory diseases in which selectins have been shown to play an important role, "where antagonism of the selectin leads to beneficial effects, in terms of decreasing damage," Rosen notes. Since the publication of this paper, he and Bertozzi have written a second review, updating ligand characterizations (S.D. Rosen, C.R. Bertozzi, Current Biology, 6:261-4, 1996). "It has a lot more on carbohydrate specificity, and it's got some new information on how one of the selectins recognizes its ligands," Rosen notes. "Sulfation is important. At the time of the first review, sulfation was known to be important for the binding of one selectin to its ligands. . . . This review points to the importance of sulfation for the ligand of another selectin. The nature of the sulfation modifications of the ligands are very different for the two selectins."

Protein Binding

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