Biological complexity: how cells remove garbage (Introduction)

by David Turell , Wednesday, September 14, 2016, 23:57 (2774 days ago) @ David Turell

There is lots because cells are constantly in production:-http://www.agnosticweb.com/index.php?mode=posting&id=22780&back=entry-"Proteins are synthesized on ribosomes as linear chains of amino acids and must fold into unique three-dimensional structures to fulfill their biological functions. Protein folding is intrinsically error-prone, and how it is accomplished efficiently represents a problem of great biological and medical importance. During folding, the nascent polypeptide must navigate a complex energy landscape. As a result, misfolded molecules may accumulate that expose hydrophobic amino acid residues and thus are in danger of forming potentially toxic aggregates. To ensure efficient folding and prevent aggregation, cells in all domains of life express various classes of proteins called molecular chaperones. These proteins receive the nascent polypeptide chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries, the proteostasis network (PN), is required to maintain protein homeostasis in a range of external and endogenous stress conditions. - "'Chaperones are a kind of Technical Inspection Authority for cells," Phys.org explains. "They are proteins that inspect other proteins for quality defects before they are allowed to leave the cell." When molecular chaperones cannot fold a protein properly in time, the surveillance crew must make a go/no-go decision, because some amino acids might clump into toxic aggregates. The "Proteostasis Network" involves cleanup crews like the proteasome system, autophagy, and the lysosome system.-***-"molecular chaperones are involved in a plethora of cellular processes by playing key roles in nascent protein chain folding, transport and quality control. Their molecular functions range from stabilizing stress-susceptible molecules and membranes to assisting the refolding of stress-damaged proteins, thereby acting as protective barriers against cellular damage.-***-"Aberrant proteins are tagged with ubiquitin, a small protein, by two independent surveillance crews. A shredding machine called the proteasome recognizes the tags and provides docking points for them. These quality-control measures ensure that only the bad proteins are degraded.-***-"A large number of different proteins in a cell have to be degraded -- some 30 percent of all cellular protein structures formed by folding of amino acid chains are faulty. The problem for the cells is that these incorrectly folded proteins do not have a uniform structure, making it difficult to identify all of them correctly. If breakdown of these "useless" proteins goes wrong, they are deposited in the cell and disturb its homeostasis. This can lead to death of the cell.-***-" The proteasome is composed of 33 subunits assembled in two sub-complexes, the 20S core particle (CP), flanked at one or both ends by the 19S regulatory particle (RP) to form the 26S proteasome. Proteasome assembly requires the assistance of proteasome assembly chaperones. Four evolutionarily conserved 19S RACs [regulatory particle assembly chaperones]: Nas2, Nas6, Hsm3 and Rpn14 in yeast, and p27 (also known as PSMD9), p28 (also known as PSMD10), S5b (also known as PSMD5) and Rpn14 (also known as PAAF1) in mammals are needed for regulatory particle assembly. In addition, yeast cells have Adc17, a stress-inducible RAC, which is vital for cells to survive conditions, such as accumulation of misfolded proteins, which overwhelm the proteasome. This suggests that cells have evolved adaptive signalling pathways to adjust proteasome assembly to arising needs, but how this is achieved is unknown.(
(My bold suggests a feedback mechanism for tight control.)-***-" Deficient proteasome function can lead to a buildup of unneeded and potentially toxic proteins, so cells usually respond to proteasome dysfunction by increasing production of its component parts. Now two Massachusetts General Hospital (MGH) investigators have identified key molecules in the pathway by which cells in the C. elegans roundworm sense proteasome dysfunction, -***-"After an egg cell is fertilized, the sperm cell's mitochondria need to be digested to prevent a condition called heteroplasmy. Maternal inheritance of mitochondria and mitochondrial genes is a major developmental paradigm in mammals. Propagation of paternal, sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals, due to postfertilization targeting and degradation of sperm mitochondria, referred to as "sperm mitophagy." Our and others' recent results suggest that postfertilization sperm mitophagy is mediated by the ubiquitin-proteasome system, the major protein-turnover pathway that degrades proteins and the autophagic pathway.... Our findings provide the mechanisms guiding sperm mitochondrion recognition and disposal during preimplantation embryo development, which prevents a potentially detrimental effect of heteroplasmy.-Comment: A high speed continuous process. We stay alive because the garbage is spotted, removed or destroyed, at 99.99% efficiency. Otherwise we die! Cells are in constant production of product or replacement molecules of cell structure. Developed by chance? Never!