The Continuing Mystery of Lipid Rafts

Abstract

Since its initial formalization nearly twenty years ago, the concept of lipid rafts has generated a tremendous amount of attention and interest, and nearly as much controversy. The controversy is perhaps surprising because the notion itself is intuitive: compartmentalization in time and space is a ubiquitous theme at all scales of biology, and therefore the partitioning of cellular membranes into lateral subdivision should be expected. Nevertheless, the physicochemical principles responsible for compartmentalization and the molecular mechanisms by which they are functionalized remain nearly as mysterious today as they were two decades ago. Herein, we review recent literature on this topic with a specific focus on the major open questions in the field, including: (1) what are the best tools to assay raft behavior in living membranes; (2) what is the function of the complex lipidome of mammalian cells with respect to membrane organization; (3) what are the mechanisms that drive raft formation and determine their properties; (4) how can rafts be modulated; (5) how is membrane compartmentalization integrated into cellular signaling. Despite decades of intensive research, this compelling field remains full of fundamental questions.

Mind the Line Tension: New Criteria for Nanodomains in Biological Membranes

“…A key question is whether this heterogeneity of the order of 10 nanometers is phase separation into coexisting liquid-ordered (Lo) and liquid-disordered (Ld) regions [2][3][4]. However, there is little experimental evidence of stable Lo domains (i.e.…”

“…However, there is little experimental evidence of stable Lo domains (i.e. lipid rafts) in live cells [2,5].…”

“…Lo domains, which form as a result of favorable enthalpic interactions between high melting temperature lipids and sterols, are thought to occur transiently and on the order of tens of nanometers in size in biological membranes [2,3]. Early studies on detergent-resistant membranes suggested certain proteins partition preferentially into Lo compartments within the plasma membrane [2,4], leading to pronounced interest in the properties and functional roles of lipid domains in nature.…”

“…Early studies on detergent-resistant membranes suggested certain proteins partition preferentially into Lo compartments within the plasma membrane [2,4], leading to pronounced interest in the properties and functional roles of lipid domains in nature. Now at 20 years since the inception of the lipid raft model [2] while the underlying basis of phase separation is clear, how this is translated in a cellular context remains obscure. The abiding mystery is sustained in large part by the inherent obstacles faced in the characterization of dynamic, nanoscopic domains in vivo [4][5][6].…”

Biophysical approaches in the study of biomembrane solubilization: quantitative assessment and the role of lateral inhomogeneity

“…These highly dynamic domains, also called lipid rafts, with sizes in the nanometer order are thought to be involved in membrane phenomena such as signal transduction, parasite infection, and intracellular trafficking of lipids and protein (Simons and Toomre 2000;Simons and Ehehalt 2002;Regen 2002;Kusumi et al 2011). The rafts theory appeared in the nineties and became as popular as controversial (Munro 2003;Lichtenberg et al 2005;Hancock 2006;Levental and Veatch 2016) by the way it addresses the well-known and biophysically-based concept of lipid heterogeneity. Also, the study of rafts in natural biological membranes has been a challenge due to the complexity of the system composition and dynamic characteristic.…”