Spatial regulation of coalesced protein assemblies: Lessons from yeast to diseases

Abstract

Organisms rely on correctly folded proteins to carry out essential functions. Protein quality control factors guard proteostasis and prevent protein misfolding. When quality control fails and in response to diverse stresses, many proteins start to accumulate at specific deposit sites that maintain cellular organization and protect the functionality of coalescing proteins. These transitions involve dedicated proteins that promote coalescence and are facilitated by endo-membranes and cytoskeletal platforms. Moreover, several proteins make use of weak multivalent interactions or conformational templating to drive the formation of large-scale assemblies. Formation of such assemblies is often associated with a change in biochemical activity that can be used by cells to execute biochemical decisions in a localized manner during development and adaption. Since all assembly types impact cell physiology, their localization and dynamics need to be tightly regulated. Interestingly, at least some of the regulatory mechanisms are shared by functional membrane-less organelles and assemblies of terminally aggregated proteins. Furthermore, constituents of functional assemblies can aggregate and become non-functional during aging. Here we present the current knowledge as to how coalescing protein assemblies are spatially organized in cells and we postulate that failures in their spatial confinement might underscore certain aspects of aging and neurodegenerative diseases.

FIGURE 1.

A. Proteins, under several physiological or pathological triggers can accumulate in deposit sites that have diverse biophysical properties. These transitions into large assemblies are controlled by chaperones, disaggregases and aggregases. Disaggregases such as Hsp104 in fungi or the Hsp40-Hsp70-Hsp110 complex in metazoans have the ability to fragment large assemblies into small oligomers that promote spreading of these aggregates. Hsp40s proteins, through their membrane attachment, enable spatial control of the coalescing proteins thereby facilitating the confinement of the assemblies and their precursors. B. In budding yeast, upon aging, aggregate precursors are collected by Ydj1 to a single deposit site localized at the ER membrane. Diffusion barriers in the ER membrane at the bud neck, involving ceramide enriched membrane domains, impair the free diffusion of certain membrane bound proteins from the aged mother cell to the rejuvenated bud. These include aggregate precursors that are attached to the ER membrane by farnesylated Ydj1. Upon prolonged pheromone treatment Whi3 forms superassemblies, yet their mode of formation and asymmetric inheritance are unknown. During aging, Whi3 also aggregates and becomes non functional.