Biological complexity: how the cell proteasome works (Introduction)

by David Turell , Tuesday, May 02, 2017, 15:37 (2762 days ago) @ dhw

Cells are constantly producing and degrading protein products. This is how the proteasome does it:

http://www.the-scientist.com/?articles.view/articleNo/49260/title/The-Proteasome--A-Pow...

"Although they are not alive themselves, proteins nonetheless progress through a life cycle of sorts: they are created by the cell, serve a specific purpose in the organism, and ultimately expire either by passive accumulation of structural defects or through active metabolic processes. As in ecological circles of life, the dead are degraded for their core components. But rather than the scavengers and microbial decomposers at work in macroscale habitats, much of the protein recycling work within the cell falls to a barrel-shaped protein complex known as the proteasome.

"Found in most known organisms, the proteasome is the crucial component of ubiquitin-mediated protein degradation. It complements the numerous proteases that degrade proteins in the cell. Protease targets can be very broad, even random, yet at the same time, the proteases themselves can be quite limited in the extent to which they break down those molecules. On the other hand, the substrate selection for the proteasome is a tightly controlled process in which chains of ubiquitins attach to proteins destined for extensive degradation by the proteasome.

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" This beefy complex is composed of more than 60 protein subunits that act together to
hydrolyze targeted proteins into short peptides of just 3 to 15 amino acids. These peptides are then broken down further into their constituent amino acids by cellular proteases.

"The proteasome can be divided into two main components, the core particle and the regulatory particles. The core particle is formed from four rings, each composed of seven subunits, that are stacked to form the proteasome’s barrel structure, which measures approximately 5 nanometers in diameter—almost as thick as the cell membrane. The two outer rings are constructed of alpha subunits that constrict the ends of the barrel to control access to the lumen. The two inner rings contain proteolytic beta subunits that degrade protein chains as they pass through. The regulatory particles form “lids” on either end of the barrel, unfolding polyubiquitinated target proteins and threading them through the narrowed opening of the core particle into the lumen. The proteasome is a two-way street; proteins can enter and exit either side.

"The proteasome is responsible for three types of ATP-dependent proteolytic activity: chymotrypsin-like, which cleaves on the carboxyl side of a target protein’s hydrophobic amino acids; trypsin-like, which chops up the carboxyl side of basic amino acids; and caspase-like, which cuts the carboxyl side of acidic amino acids. Each of these protease activities is encoded in separate beta subunits in the core particle—β5, β2, and β1 subunits, respectively. Despite targeting different parts of a protein for cleavage, all of these subunits act via a similar mechanism: a threonine residue in each β subunit attacks the peptide bond of its target amino acid.....in order to keep the proteasome from degrading itself during its initial assembly, these reactive threonine residues are masked by protective amino acids that are snipped off in the final assembly step.

"Specialized proteasomes are structurally similar to the constitutive proteasome, but do have some unique alpha and beta subunits that impart functional differences. For example, due to its beta subunits β1i, β2i, and β5i, immunoproteasomes have dramatically reduced caspase-like proteolytic activity and greatly increased chymotrypsin-like activity, which is believed to assist in creating peptide fragments that are better suited for binding to the major histocompatibility complex during antigen presentation.

"Conversely, the thymoproteasome-specific β5 subunit (β5t) gives that complex much lower chymotrypsin-like activity than constitutive proteasomes, a difference that appears to be instrumental for the thymus to select CD8+ T cells for survival and maturation. Knockout mice that lack β5t lose more than 80 percent of their cytotoxic CD8+ T cells and succumb to infections that wild-type mice overcome.2 Finally, the altered alpha subunit composition of the spermatoproteasome may contribute to the degradation of acetylated core histones, an important step in chromosome condensation during spermatid differentiation and spermatogenesis."

Comment: The proteasome protects itself from self-degradation and is specialized for different organ functions and for different immunologic activities. No cell can operate without this organelle. The original cells at the start of life had to have a portion of it that maintained this action. Only design can provide all the interactive parts of the original cells. The complexity shows this.