Biological complexity: removing cellular garbage (Introduction)

by David Turell , Tuesday, May 23, 2023, 18:07 (340 days ago) @ David Turell

Another study:

https://phys.org/news/2023-05-reveal-nanomachine-cell.html

"Have you ever put off cleaning the house or decluttering the overflowing basement? Living cells cannot afford this procrastination when it comes to clearing the decks. Tiny garbage chutes are constantly active there to capture worn-out proteins, faulty cell components, or defective organelles. These garbage chutes, called autophagosomes, pick out the discarded components before they accumulate in the cell and cause damage. The cellular waste is then passed on to the cell's own recycling machinery, the lysosome, where it is digested and recycled.

"Thus, building blocks for new cellular components are quickly available again. The autophagy process, literally self-eating, thus also helps cells to survive stress or periods of starvation.

"Autophagy also serves another important purpose. It renders harmless viruses and bacteria that successfully bypass the immune system's defenses and reach the cell plasma. The consequences are correspondingly fatal if the autophagy process is faulty, too slow, or too fast.

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"'Autophagy is a highly complex process involving many different proteins and protein complexes. We know many of them, but there are still fundamental gaps in our knowledge," reports Alex Faesen, research group leader at the Max Planck Institute for Multidisciplinary Sciences in Göttingen. "How do the protein components work together? How is the process of autophagy started and stopped? When and where is the autophagosome assembled? That is what we want to find out."

***

"...the team brought the individual protein complexes together. "The complexes self-assembled into a protein supercomplex, the autophagy initiation complex. In fact, autophagy involves a sophisticated cellular nanomachine—and it works quite differently than previously thought," the group leader says.

"To make autophagosomes, the autophagy initiation complex first creates a junction between a particular structure of the cell, the endoplasmic reticulum, and the autophagosome that forms. Under stress or in times of starvation, such as during endurance sports, this occurs within just a few minutes. "From this point on, there is no turning back: The waste disposal is assembled and collects the cellular waste," explains Anh Nguyen, one of the two first authors of the study.

"Co-first author Fancesca Lugarini adds, "Via the contact site, fat-like molecules called lipids are transported to a precursor stage of autophagosomes, where they are incorporated." These grow and, in the process, enclose the cell material to be disposed of—the finished mini-organelle is formed. Within barely 20 minutes of its formation, the autophagosome is already delivering its waste to the lysosome by fusing with it.

"But what starts the assembly of the autophagy machine, what starts it and what stops it? The researchers did not find a molecular "on" and "off" switch as in other molecular machines. Instead, the switch uses a highly unusual behavior of proteins: metamorphosis. Certain molecules, called ATG13 and ATG101, have the ability to fold in different 3D structures, thereby changing its ability to bind to proteins in the machine. "This protein metamorphosis also gives the go-ahead for the assembly of the autophagy initiation complex at the right time and in the right place," says Faesen, describing the special features of the nanomachine. Without metamorphosis, the initiation machine does not assemble."

Comment: Amazing. These changeable chameleon molecules must carefully select only what is garbage in their disposal process to keep the living cell functional. This process as so many pars it is irreducibly complex and must have been designed.