Weak Ergodicity Breaking of Membrane Receptor Motion Stemming from Random Diffusivity

Abstract

The application of techniques such as fluorescence correlation spectroscopy and single particle tracking to the plasma membrane of living cells continuously evidences subdiffusive motion of proteins and lipids. This anomalous motion is generally associated to the interplay of molecular crowding, diffusion barriers and specific interactions. Addressing the cause of subdiffusion is essential for understanding molecular mechanisms underlying cellular function, such as target search, kinetics of transport-limited reactions, trafficking and signalling. Recently, the subdiffusive motion of some cellular and membrane components has been associated to weak ergodicity breaking and attributed to transient immobilization caused by interactions with microtubules or actin cytoskeleton. These works have opened new questions about the role of nonergodic subdiffusion in the dynamics of living systems.By means of single particle tracking experiments, we show that the dynamics of DC-SIGN, a transmembrane receptor with unique pathogen recognition capabilities, also reveals subdiffusion with signatures of weak ergodicity breaking and aging. In contrast to other biological systems, we demonstrate that DC-SIGN nonergodic subdiffusion cannot be explained by transient immobilization, but rather is compatible with dynamical heterogeneity induced by spatiotemporal changes of diffusivity. While nonergodic diffusion due to long-lived immobilization events can be understood within the framework of continuous-time random walk, our experimental data are accurately interpreted through a new theoretical model describing anomalous transport in biological systems and complex media. A comprehensive analysis of mutated forms of the receptor allowed us to establish a link between receptor molecular structure, nonergodic diffusion and function. Our results underscore the role of spatiotemporal disorder in the dynamics of cell membrane receptors. In addition, they have broad implications to other heterogeneous systems where the occurrence of nonergodicity remains unexplored.