Researchers decipher critical features of a protein behind ALS
The Sigma-1 receptor (S1R) is a transmembrane protein with important roles in stabilizing cellular functions in both normal physiology and disease. Especially in neurodegenerative diseases, S1R's activity has been shown to provide neuronal protection by stabilizing the cell environment (based on the movement of calcium ions), improving mitochondrial function and reducing a damaging cellular stress caused by the diseases, called endoplasmic reticulum stress. Drugs are now being developed to try to boost these cell protective S1R activities in several diseases.
S1R missense mutations are one of the causes of distal hereditary motor neuronopathies and amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease). ALS is the ailment that afflicted renown late physicist Stephen Hawking. Yet, even though S1R has been studied intensively, basic aspects remained controversial, such as S1R topology and whether it reaches the cell membrane.
A new study led by Tel-Aviv University researcher Gerardo Lederkremer from the Shmunis School of Biomedicine and Cancer Research and Sagol School of Neuroscience, together with Nir Ben Tal from the School of Neurobiology, Biochemistry and Biophysics, and students in their labs, sheds light on some of these important questions. The study was recently published in the Journal of Biological Chemistry.
“Proteins, much like a bipolar magnet, have two ends — carboxy (-COOH group) and amino (-NH2 group)," said Lederkremer. "In one trial, we tagged the carboxy end (C-terminal tagging) and found that the protein is set in a specific orientation on internal membranes of the cell, where the amino end faces the cytoplasm. In another approach, we tagged the amino end and found equal probability for both possible orientations.”
These findings provide an explanation for current contradictions in the literature regarding the favored orientation, as the tagging itself affects the receptor’s topology — “an act of observation which affects the observed system.” Therefore, said Lederkremer, “we applied other approaches, called protease protection assay and glycosylation mapping, which showed incontrovertibly that S1R assembles so that the amino end faces the cytoplasm. Moreover, using additional approaches we found that the receptor is retained in the ER and hardly exits to the cell surface. This finding explains how the S1R functions in the ER and reduces the pathogenic ER stress”.
Lederkremer said he is optimistic about the new findings: “Having deciphered a crucial mechanism in the receptor's function, we have no doubt that our new findings can affect therapeutic approaches based on S1R, and hopefully alleviate the suffering of neurodegenerative patients, especially those with ALS. In this field every small step is a significant advance.”
This article was reprinted with permission from Tel Aviv University. Read the original.
Enjoy reading ASBMB Today?
Become a member to receive the print edition four times a year and the digital edition weekly.
Learn moreGet the latest from ASBMB Today
Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.
Latest in Science
Science highlights or most popular articles
Gene-mutation pathway discovery paves way for targeted blood cancers therapies
A new study by researchers at the universities of Texas and Chicago explains the enzymatic activity that’s needed for tumor suppression in leukemias and other cancers.
Candy binges can overload your gut microbiome
While most Halloween candies contain lots of sugar, some are better for your gut microbiome than others.
Water rescues the enzyme
“Sometimes you must bend the rules to get what you want.” In the case of using water in the purification of calpain-2, it was worth the risk.
Virtual issue celebrates water in ASBMB journals
Read a dozen gold open-access articles covering exciting research about the society’s 2024 Molecule of the year.
There are worse things in the water than E. coli
E. coli levels determined whether Olympic swimmers could dive into the Seine this past summer. But are these bacteria the best proxy for water contamination?
Biobots arise from the cells of dead organisms
Given the right conditions, certain types of cells are able to self-assemble into new lifeforms after the organism they were once part of has died.