Switching immune signals on and off

Bruton's tyrosine kinase, an enzyme that is important for B cell function, can be activated in a number of ways. Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate. eLife 4:e06074. Image The enzyme Btk has crucial roles in tyrosine kinase signaling and the development of certain immune cells B cells are immune cells that protect the body against pathogens by making antibodies that mark the pathogens for destruction. B cells are activated by signals that are produced when enzymes called non-receptor tyrosine kinases help to phosphorylate proteins inside the B cells. One such enzyme is Bruton's tyrosine kinase (Btk), and mutations in this enzyme are known to cause an immunodeficiency disease called X-linked agammaglobulinemia (Rawlings et al., 1993; Thomas et al., 1993). People with this disease completely lack B cells, have low levels of antibodies, and experience recurring infections (Aalipour and Advani, 2013). Hyperactive Btk also contributes to disease, causing cancerous B cells to proliferate, and this has motivated the development of drugs that target Btk. For example, the FDA-approved drug ibrutinib is an irreversible inhibitor of Btk (Honigberg et al., 2010) and is used to treat cancers such as mantle cell lymphoma and chronic lymphocytic leukemia (Aalipour and Advani, 2013). as first author—have used a series of elegant structural and biochemical approaches to identify unexpected new features of the molecular basis of Btk inhibition and activation (Wang et al., 2015). Btk is composed of a series of different domains. The kinase domain, which catalyzes the phosphorylation of proteins, is connected via domains called SH2 and SH3 to the PH-TH domain (Figure 1). While the three-dimensional structures of the isolated Btk domains have previously been determined, it has not been clear how these domains interact with each other and how they regulate the kinase domain. It has been proposed that Btk is recruited to cellular membranes by a molecule embedded in the membrane called phosphatidyl inositol triphos-phate (PIP3). This phospholipid engages with the PH-TH domain, and somehow activates the Btk kinase domain so that it phosphorylates itself and/or causes it to be activated by other tyrosine kinases (Mohamed et al., 2009). Wang et al. have now solved the high-resolution crystal structures of two molecules made up of several of the Btk domains: SH3-SH2-kinase and PH-TH-kinase. These structures provide molecular details of the interactions between the Btk domains that can explain Btk autoinhibition—the ability of Btk to inhibit itself. …