Understanding the Role of the Endoplasmic Reticulum in Cellular Recycling
Within cells, there is a vast network of channels called the endoplasmic reticulum (ER), made up of membrane-bound tubes that can be partially dissolved when necessary, such as during periods of nutrient scarcity. During this process, the membrane can bulge outward, eventually pinching off to be recycled by the cell. A recent study conducted by scientists at Goethe University Frankfurt explored this bulging process using computer simulations, revealing that specific structural features of proteins in the ER membrane are crucial to this mechanism. This research was part of the “SCALE — Subcellular Architecture of Life” initiative.
The endoplasmic reticulum serves multiple purposes, including storing calcium and carbohydrates, as well as producing various hormones. Cells can adapt the growth and interconnections of their internal canal systems based on their needs. A vital part of this adjustment is a process called ER-phagy (“ER-eating”), where a segment of the ER membrane bulges outward and ultimately forms a small vesicle. Meanwhile, an autophagosome, which acts like an internal “trash bag,” forms around the vesicle. This structure then fuses with another compartment filled with highly active enzymes that break down and recycle the contents of the “trash bag.”
“We have known for several years that specific proteins, known as ER-phagy receptors, are essential to this process,” says Dr. Ramachandra Bhaskara from Goethe University’s Institute of Biochemistry II. These receptors reside in the ER membrane and have an anchor that embeds into it, with two long protein chains that extend away from the membrane like flexible tentacles. “Through complex simulations on supercomputers, we have recently demonstrated, along with other research teams, that this anchor causes the membrane to curve,” Bhaskara explains. He adds that “under certain circumstances, this can lead to a bulge formation. Our current study shows that the filament-like structures increase the probability and significantly speed up the creation of such bulges.”
Proteins Create Disordered “Tentacles” from Amino Acids
Most proteins take on specific three-dimensional shapes after they are synthesized: some regions form twisted helical structures, while others fold back and forth like an accordion bellows. This results in a compact and relatively rigid configuration, which is also true for the anchor portion of ER-phagy receptors. However, the tentacles consist of lengthy amino acid chains that move in a largely chaotic manner—hence they are called “intrinsically disordered (protein) regions” or IDRs. These extensive movements require space, which they generate by pushing the membrane outward. “An additional factor,” highlights Dr. Sergio Alejandro Poveda Cuevas, the lead author of the study, “is that IDRs have short segments that can fold back under specific conditions. We showed that this folding occurs during bulge formation, allowing them to fit against the membrane like a support structure, reinforcing its curve.”
The process of pinching off involves several precisely coordinated actions, as illustrated by the simulations: initially, the anchor areas of various ER-phagy receptors come together. This clustering heightens the curvature of the membrane created by the receptors. Initially, the IDR tentacles stretch out, contacting the autophagy machinery to guide it toward the membrane. The IDRs then compact into tighter structures, further enhancing the bulge until the membrane finally pinches off, encapsulated within the autophagosome (“trash bag”).
Research Could Inform Treatments for Certain Diseases
“Alongside providing a thorough insight into this critical cellular process, our study highlights the significant role of receptor IDRs in ensuring smooth operation,” explains Bhaskara. These findings are especially noteworthy, as some inherited neurological disorders are linked to disrupted ER-phagy. Improved comprehension of membrane degradation processes may eventually allow for targeted interventions.
This research received support from the German Research Foundation (DFG) under Collaborative Research Center 1177 and the ENABLE cluster initiative funded by the Hessian Ministry of Science, Research, Arts, and Culture.