Protein homeostasis: live long, won't prosper

Abstract

Protein turnover is an effective way of maintaining a functional proteome, as old and potentially damaged polypeptides are destroyed and replaced by newly synthesized copies. An increasing number of intracellular proteins, however, have been identified that evade this turnover process and instead are maintained over a cell's lifetime. This diverse group of long-lived proteins might be particularly prone to accumulation of damage and thus have a crucial role in the functional deterioration of key regulatory processes during ageing.

Figure 1

Long-lived proteins and the accumulation of damage. Most proteins participate in a constant cycle of synthesis and degradation. Some proteins, however, evade degradation and are long-lived. Due to their longevity, these long-lived proteins are more prone to the accumulation of damage, which can lead to impaired protein function and cellular ageing.

Figure 2

Eye lens structure. a) The position of the eye lens is depicted in a cross-section of the eye, as well as the general organization of lens structure (inset). The eye lens experiences radial growth, with the older lens fiber cells residing in the center and the younger cells on the outer rings. b) Lens cells through ageing. As the eye lens ages, long-lived crystallin molecules accumulate damage, leading to their aggregation into larger ordered structures which disrupts their transparency properties.

Figure 3

Schematic of the nuclear pore complex. The NPC is embedded in a double membrane structure separating the nucleus and cytoplasm. It is composed of several subcomplexes, including the peripheral, membrane, channel FG, and scaffold Nups. Whereas the peripheral, channel, and membrane Nups turnover continuously, the scaffold Nups are stable. We propose this stability is necessary and that rapid exchange or loss of these components would result in a disrupted permeability barrier. Thus, maintenance or turnover of these scaffold complexes is necessarily slow, if at all.