Nucleocytoplasmic transport: a thermodynamic mechanism

TL;DR

This paper investigates the thermodynamic principles underlying nucleocytoplasmic transport, revealing capacity limits, the non-deterministic role of the pore, and the importance of chemical partitioning in establishing concentration gradients.

Contribution

It introduces a combined analytical and experimental model demonstrating how chemical partitioning governs transport capacity and challenges existing transport cycle concepts.

Findings

Transport capacity is limited, causing cargo egress when new cargo is introduced.

Transport directionality is not solely determined by the nuclear pore.

Cargo reach similar steady-state ratios independent of receptor-cargo affinity.

Abstract

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.