title: Dimerization of visinin-like protein 1 is regulated by oxidative stress and calcium and is a pathological hallmark of amyotrophic lateral sclerosis.
abstract: Redox control of proteins that form disulfide bonds upon oxidative challenge is an emerging topic in the physiological and pathophysiological regulation of protein function. We have investigated the role of the neuronal calcium sensor protein visinin-like protein 1 (VILIP-1) as a novel redox sensor in a cellular system. We have found oxidative stress to trigger dimerization of VILIP-1 within a cellular environment and identified thioredoxin reductase as responsible for facilitating the remonomerization of the dimeric protein. Dimerization is modulated by calcium and not dependent on the myristoylation of VILIP-1. Furthermore, we show by site-directed mutagenesis that dimerization is exclusively mediated by Cys187. As a functional consequence, VILIP-1 dimerization modulates the sensitivity of cells to an oxidative challenge. We have investigated whether dimerization of VILIP-1 occurs in two different animal models of amyotrophic lateral sclerosis (ALS) and detected soluble VILIP-1 dimers to be significantly enriched in the spinal cord from phenotypic disease onset onwards. Moreover, VILIP-1 is part of the ALS-specific protein aggregates. We show for the first time that the C-terminus of VILIP-1, containing Cys187, might represent a novel redox-sensitive motif and that VILIP-1 dimerization and aggregation are hallmarks of ALS. This suggests that VILIP-1 dimers play a functional role in integrating the cytosolic calcium concentration and the oxidative status of the cell. Furthermore, a loss of VILIP-1 function owing to protein aggregation in ALS could be relevant in the pathophysiology of the disease.
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Martina P
authors.initials: MP
authors.lastname: Liebl
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Kaya
authors.affiliation: Institute for Immunology, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Romy
authors.initials: R
authors.lastname: Mittenzwei
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Koziollek-Drechsler
authors.affiliation: Institute for Immunology, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Moosmann
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behl
authors.affiliation: Institute for Pathobiochemistry, University Medical Center, Johannes Gutenberg University, D-55099 Mainz, Germany. Electronic address: clement@uni-mainz.de.
authors.forename: Albrecht M
authors.initials: AM
authors.lastname: Clement
mesh_terms: D020816:Amino Acid Motifs; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D051596:Neurocalcin / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D055503:Protein Multimerization; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D051596:Neurocalcin; C000606290:SOD1 protein, human; C496688:VSNL1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium
keywords: Amyotrophic lateral sclerosis; Cysteine; Free radicals; Redox sensor; VILIP-1