Why nature evolved GPI-anchored proteins: unique structure characteristics enable versatile cell surface functions

It remains a mystery why nature evolved the unique structural characteristics of GPI-anchored proteins (GPI-APs) and continues to sustain the complex, energy-intensive process of synthesizing these proteins. GPI-APs, despite their small size, rely on the coordinated activity of nearly 30 genes for their synthesis and remodeling, raising important evolutionary questions. The biological advantages of GPI-APs lie in their ability to rapidly redistribute across the cell membrane, localize within lipid rafts, utilize unique intracellular trafficking pathways, and function as both membrane-bound and soluble proteins. These properties allow GPI-APs to participate in diverse cellular processes such as synaptic plasticity, immune regulation, and signal transduction, highlighting their indispensable roles. Additionally, the shedding capability of GPI-APs extends their functional reach, adding further versatility to their biological roles. This review not only summarizes these key insights but also explores the broader implications of GPI-APs in cell signaling and disease. By understanding the evolutionary necessity of GPI-APs, we can better appreciate their complexity and potential as therapeutic targets.