Lipid targeting domain with dual-membrane specificity that expands the diversity of intracellular targeting reactions

Abstract

In cell signaling pathways, many critical on-off switching events occur on membrane surfaces. Such switching events are often regulated by lipid targeting domains that recruit their parent signaling proteins from cytoplasm to the appropriate membrane surface during the event and then release from the membrane when the event ends. Once bound to their target membrane, the recruited signaling proteins are activated, at least in part, by enhanced accessibility to membrane-associated effector proteins and/or lipids (Fig. 1A). Lipid targeting domains have evolved sophisticated chemical recognition strategies to discriminate among diverse types of membranes exposed to the cytoplasm, enabling specific binding to one membrane. Progress is being made toward understanding the recognition mechanisms that deliver lipid targeting domains and their parent signaling proteins to exactly the right membrane surface at precisely the right time. However, the article by Boura and Hurley (1) in PNAS suggests that even more complex, highly specialized membrane targeting specificities remain to be discovered. The article reports the very high resolution (1.3 A) crystal structure of the recently described (2) MVB12-associated β-prism (MABP) domain and shows that the MABP domain targets anionic lipid bilayers. Further, in live cells, a homodimeric construct of the domain exhibits an unusual dual specificity characterized by simultaneous targeting to the plasma membrane and late endosomes, consistent with the known activity of MVB12 and its ESCRT complex (Endosomal Sorting Complex Required for Transport) at both membranes. This first observation of dual-membrane targeting raises intriguing questions about the mechanism by which such targeting is achieved.