Spatial control of irreversible protein aggregation.

Christoph Weber,L Mahadevan,Thomas Michaels

doi:10.7554/elife.42315

Abstract

Liquid cellular compartments form in the cyto- or nucleoplasm and can regulate aberrant protein aggregation. Yet, the mechanisms by which these compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that even for weak interactions aggregates strongly partition into the liquid compartment. Aggregate partitioning is caused by a positive feedback mechanism of aggregate nucleation and growth driven by a flux maintaining the phase equilibrium between the compartment and its surrounding. Our model establishes a link between specific aggregating systems and the physical conditions maximizing aggregate partitioning into the compartment. The underlying mechanism of aggregate partitioning could be used to confine cytotoxic protein aggregates inside droplet-like compartments but may also represent a common mechanism to spatially control irreversible chemical reactions in general.

Highlights

Spatial control within living cells is essential to many cellular activities, ranging from the local control of protein activity to the uptake of pathogens or the management of wastes (Alberts, 2017)
For non-fragmenting systems with n2 > 0, our model predicts different scenarios for aggregating systems: largest aggregate partitioning for large compartment volumes occurs in the case branching systems, such as actin in the presence of the complex Arp2/3, as well as systems proliferating through monomer dependent secondary nucleation with n2 < n1 À 1, such as the Islet Amyloid Polypeptide (IAPP)
Compartment volume and monomer partitioning control the total amount of aggregates Our results have demonstrated that aggregates can be effectively partitioned inside liquid-like compartments, raising the question: can compartments control the total amount of aggregates or their average size? To test this possibility, we compute the difference between the total amount of aggregates formed in the presence of liquid compartments, ctaot 1⁄4 ÀcIað¥ÞVI þ cIaIð¥ÞVIIÁ=V, compared to the number of aggregates formed in the homogeneous system without compartments, ctaotjfI1⁄4fII

Summary

Introduction

Spatial control within living cells is essential to many cellular activities, ranging from the local control of protein activity to the uptake of pathogens or the management of wastes (Alberts, 2017). For non-fragmenting systems with n2 > 0, our model predicts different scenarios for aggregating systems: largest aggregate partitioning for large compartment volumes occurs in the case branching systems, such as actin in the presence of the complex Arp2/3, as well as systems proliferating through monomer dependent secondary nucleation with n2 < n1 À 1, such as the Islet Amyloid Polypeptide (IAPP). For low partitioning factors G, the presence of liquid compartments decreases the total number of aggregates, corresponding to a larger average aggregate size, while for larger values of G, more and thereby shorter aggregates form compared to the homogeneous system (Figure 5(b)) This behavior is affected by compartment volume; the corresponding boundary in the f-G diagram separates these two regimes corresponding to more but smaller or less but larger aggregates (Figure 5(c)). A strong partitioning of aggregates inside compartments caused by a strong monomer partitioning (large G) is accompanied by an increase of the total number of aggregates in the system in the presence of secondary nucleation, while in the absence of secondary nucleation, the total amount of aggregates decreases

Discussion

Funding Funder Deutsche Forschungsgemeinschaft