Spatiotemporal model of a key step in endocytosis: SNX9 recruitment via phosphoinositides

TL;DR

This paper presents a computational model of endocytic protein and phosphoinositide dynamics, revealing how lipid binding affinities and competition lead to SNX9 enrichment during vesicle formation.

Contribution

The study introduces a detailed spatiotemporal model of protein-lipid interactions in endocytosis, highlighting mechanisms of SNX9 recruitment via phosphoinositide signaling.

Findings

SNX9 is selectively enriched at late-stage CCPs due to PI(3,4)P2 production.

Small differences in lipid affinity are amplified by competition among proteins.

The model captures complex protein-lipid interactions within endocytic sites.

Abstract

Clathrin mediated endocytosis (CME) is an ubiquitous cellular pathway that regulates central aspects of cell physiology such as nutrient uptake, modulation of signal transduction, synaptic transmission and membrane turn-over. Endocytic vesicle formation depends on the timed production of specific phosphoinositides and their interactions with various endocytic proteins. Recently, it has been found that phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) produced by the class II phosphatidylinositol 3-kinase C2alpha plays a key role in the recruitment of the PX-BAR domain protein SNX9, which is proposed to play a role in the constriction of the endocytic vesicle neck [Posor et al, Nature 499, p233 (2013)]. Interestingly, SNX9 and its close paralog SNX18 are not fully specific to PI(3,4)P2 but can also bind other phospholipids, in particular to PI(4,5)P2, an abundant plasma membrane lipid required for the recruitment of many endocytic proteins. In order to understand the dynamical interplay between phospholipids and endocytic proteins, we developed a computational model of the temporal changes in the population of the phosphoinositide-associated endocytic proteins and their spatial distribution at a clathrin-coated pit (CCP). The model resolves single molecules in time and space, and incorporates the complex interplay of proteins and lipids, as well as their movement within the CCP. We find that the comparably small differences in lipid binding affinities of endocytic proteins are amplified by competition among them, allowing for the selective enrichment of SNX9 at late stage CCPs as a result of timed PI(3,4)P2 production.