Mechanism for transforming cytosolic SOD1 into integral membrane proteins of organelles by ALS-causing mutations
- PMID: 25306968
- DOI: 10.1016/j.bbamem.2014.10.002
Mechanism for transforming cytosolic SOD1 into integral membrane proteins of organelles by ALS-causing mutations
Abstract
Mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (FALS), while wild-type SOD1 has been implicated in sporadic ALS (SALS). SOD1 mutants are now recognized to acquire one or more toxicities that include their association with mitochondrial and endoplasmic reticulum membranes but the underlying structural mechanism remains unknown. Here we determine NMR conformations of both wild-type and a truncation mutant (L126Z) of SOD1 in aqueous solution and a membrane environment. The truncation mutant (which causes FALS at very low levels, indicating its elevated toxicity) is highly unstructured in solution, failing to adopt the β-barrel SOD1 native structure. Wild-type SOD1 is also highly unstructured upon reduction of disulfides and depletion of zinc. Most remarkably, both mutant and wild type adopt similar, highly-helical conformations in a membrane environment. Thus, either truncation or depletion of zinc is sufficient to eliminate the native β-barrel structure, and transform cytosolic SOD1 into membrane proteins energetically driven by forming amphiphilic helices in membranes. That zinc-deficiency is sufficient to produce a similar transformation in wild-type SOD1 implies that the wild-type and FALS-linked SOD1 mutants may trigger ALS by a common mechanism.
Keywords: Amphiphilicity; Amyotrophic lateral sclerosis (ALS); Membrane protein; NMR spectroscopy; Superoxide dismutase 1 (SOD1).
Copyright © 2014 Elsevier B.V. All rights reserved.
Similar articles
-
SALS-linked WT-SOD1 adopts a highly similar helical conformation as FALS-causing L126Z-SOD1 in a membrane environment.Biochim Biophys Acta. 2016 Sep;1858(9):2223-2230. doi: 10.1016/j.bbamem.2016.06.027. Epub 2016 Jul 1. Biochim Biophys Acta. 2016. PMID: 27378311
-
The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation.J Biol Chem. 2015 Dec 18;290(51):30624-36. doi: 10.1074/jbc.M115.666503. Epub 2015 Oct 28. J Biol Chem. 2015. PMID: 26511321 Free PMC article.
-
Metalation of the amyotrophic lateral sclerosis mutant glycine 37 to arginine superoxide dismutase (SOD1) apoprotein restores its structural and dynamical properties in solution to those of metalated wild-type SOD1.Biochemistry. 2007 Sep 4;46(35):9953-62. doi: 10.1021/bi700620r. Epub 2007 Aug 7. Biochemistry. 2007. PMID: 17683122
-
Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis.Annu Rev Biochem. 2005;74:563-93. doi: 10.1146/annurev.biochem.72.121801.161647. Annu Rev Biochem. 2005. PMID: 15952898 Review.
-
Oxidized/misfolded superoxide dismutase-1: the cause of all amyotrophic lateral sclerosis?Ann Neurol. 2007 Dec;62(6):553-9. doi: 10.1002/ana.21319. Ann Neurol. 2007. PMID: 18074357 Review.
Cited by
-
Molecular Mechanisms of Phase Separation and Amyloidosis of ALS/FTD-linked FUS and TDP-43.Aging Dis. 2024 Oct 1;15(5):2084-2112. doi: 10.14336/AD.2023.1118. Aging Dis. 2024. PMID: 38029395 Free PMC article. Review.
-
Extreme diversity of 12 cations in folding ALS-linked hSOD1 unveils novel hSOD1-dependent mechanisms for Fe2+/Cu2+-induced cytotoxicity.Sci Rep. 2023 Nov 14;13(1):19868. doi: 10.1038/s41598-023-47338-8. Sci Rep. 2023. PMID: 37964005 Free PMC article.
-
ATP induces folding of ALS-causing C71G-hPFN1 and nascent hSOD1.Commun Chem. 2023 Sep 5;6(1):186. doi: 10.1038/s42004-023-00997-0. Commun Chem. 2023. PMID: 37670116 Free PMC article.
-
Adenosine triphosphate energy-independently controls protein homeostasis with unique structure and diverse mechanisms.Protein Sci. 2021 Jul;30(7):1277-1293. doi: 10.1002/pro.4079. Epub 2021 Apr 13. Protein Sci. 2021. PMID: 33829608 Free PMC article. Review.
-
The metal cofactor zinc and interacting membranes modulate SOD1 conformation-aggregation landscape in an in vitro ALS model.Elife. 2021 Apr 7;10:e61453. doi: 10.7554/eLife.61453. Elife. 2021. PMID: 33825682 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous