The ALS-related σ1R E102Q Mutant Eludes Ligand Control and Exhibits Anomalous Response to Calcium

Autor: Pilar Sánchez-Blázquez, Javier Garzón-Niño, María Rodríguez-Muñoz, Elsa Cortés-Montero
Rok vydání: 2020
Předmět:
Protein Conformation
Endoplasmic Reticulum
Ligands
Quantitative Biology::Cell Behavior
lcsh:Chemistry
Mutant protein
lcsh:QH301-705.5
Spectroscopy
biology
Voltage-dependent calcium channel
Quantitative Biology::Molecular Networks
General Medicine
Transmembrane protein
Computer Science Applications
Cell biology
Mitochondria
Binding immunoglobulin protein
N-methyl-D-aspartate receptor
Calmodulin
chemistry.chemical_element
Calcium
Catalysis
Article
Quantitative Biology::Subcellular Processes
Inorganic Chemistry
juvenile amyotrophic lateral sclerosis
Animals
Humans
Receptors
sigma
Physical and Theoretical Chemistry
sigma type receptor 1
Molecular Biology
Calcium metabolism
Endoplasmic reticulum
E102Q mutation
binding immunoglobulin protein
fungi
Organic Chemistry
Amyotrophic Lateral Sclerosis
Calcium
Dietary
transient receptor potential calcium channels
chemistry
lcsh:Biology (General)
lcsh:QD1-999
Mutation
biology.protein
bacteria
Calcium Channels
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 21, Iss 7339, p 7339 (2020)
Volume 21
Issue 19
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1422-0067
Popis: Sigma receptor type 1 (&sigma
1R) is a transmembrane protein expressed throughout the central nervous system and in certain peripheral tissues. The human &sigma
1R E102Q mutation causes juvenile amyotrophic lateral sclerosis (ALS), likely by inducing a series of alterations in calcium efflux from the endoplasmic reticulum (ER) to mitochondria that affects calcium homeostasis and cellular survival. Here, we report the influence of calcium on &sigma
1R E102Q associations with glutamate N-methyl-D-aspartate receptors (NMDARs), binding immunoglobulin protein (BiP), and transient receptor potential calcium channels A1, V1, and M8. The mutant protein inhibited the binding of calmodulin to these calcium channels and interacted less with BiP than wild-type &sigma
1R, thereby contributing to calcium homeostasis dysfunction. Mutant &sigma
1R, but not wild-type &sigma
1R, strongly bound to histidine triad nucleotide binding protein 1, which regulates neuromuscular synaptic organization and target selection through teneurin 1. While ligands regulated the association of &sigma
1R wild-type with NMDARs and BiP, they failed to modulate the interaction between these proteins and the &sigma
1R E102Q mutant. Thus, the &sigma
1R E102Q mutant exhibited an anomalous response to cytosolic calcium levels, altered affinity for target proteins, and a loss of response to regulatory ligands. We believe that these modifications may contribute to the onset of juvenile ALS.
Databáze: OpenAIRE
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