Several studies now show that certain proteins exhibit selective preference toward liquid ordered (L[Formula: see text]) or toward liquid disordered (L[Formula: see text]) regions of the heterogeneous membrane and some of them have preference for the L[Formula: see text]-L[Formula: see text] interface. Spatially heterogenous organization of lipids, enriched in specific protein molecules, function as platforms for signaling and are involved in several other physiologically critical functions. In this review, we collate together some of the experimental observations of cases where proteins preferentially segregate into different phases and highlight the importance of these preferential localization in terms of underlying functions. We also try to understand the structural features and chemical makeup of the membrane-interacting motifs of these proteins. Finally, we put forth some preliminary analysis on class I viral fusion proteins, some of which are known to partition at the L[Formula: see text]-L[Formula: see text] interface, and through them we try to understand the evolutionary design principles of phase segregating proteins. Put together, this review summarizes the existing studies on preferential partitioning of proteins into different membrane phases while emphasizing the need to understand the molecular design-level features that can help us "engineer" functionally rich peptides and proteins with a programmed membrane partitioning.
Keywords: Lipid nanodomain; Liquid–liquid phase separation in membrane; Preferential protein partitioning; Viral fusion peptides.