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Amyotrophic Lateral Sclerosis and Superoxide Dimutase 1 (SOD1) Iasson Yi CHEM 4700
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ALS Lou Gehrig’s Disease Progressive neurodegenerative disease Affects nerve cells in the brain and spinal cord Motor neurons
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ALS - Symptoms Muscle weakness Twitching (fasciculation) and cramping Shortness of breath, difficulty in breathing and swallowing Ice bucket challenge https://alsrideforlife.org/support-us/
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ALS - Genetics Chromosome 21 – Gene SOD1 Many point mutations Mutations in protein regions Influence architectural integrity
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ALS - Treatment No cure Riluzole – slows down the progression of the disease (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700231/)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700231/ Areas of research – miRNA (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781640/)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781640/ – Stem cell-derived motor neurons (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887342/)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887342/
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SOD 1 Superoxide Dimustase, Cu, Zn (aka SOD1) Oxidoreductase CATH Superfamily 2.60.40.200 Functional family – Superoxide dismutase – like domain
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SOD1 - Mechanism Converts harmful superoxide radicals to oxygen and hydrogen peroxide www.intechopen.com/books/current-advances-in-amyotrophic-lateral- sclerosis/superoxide-dismutase-and-oxidative-stress-in-amyotrophic- lateral-sclerosis
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General view
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Protein characteristics 10 chains 153 amino acids per chain Cu + ligand Zn 2+ ligand SO 4 2- residues X-ray diffraction Resolution: 2.40 angstroms
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Secondary structure
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3 alpha helices (9%) 9 beta strands (37.7%) 53.3% neither
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Motifs Beta hairpins Beta meander
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Motifs Beta barrel?
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Disulfide bond
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Active site - Ligands contacts Cu ligand: – His 46 – His 48 – His 63 – His 120 Zn ligand – His 63 – His 71 – His 80 – Asp 83
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Active site – electrostatic loop – zinc loop http://health-innovations.org/2014/10/15/scientists-link-als-progression-to-increased-protein- instability/
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ALS – Secondary structure 1 alpha helix (3.3%) 8 beta strands (30.7%) 66% neither
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ALS – Active site – Ligands contacts Cu ligand – His 46 – His 48 – His 63 – His 120 Zn ligand – His 63 – His 71 – His 80 – Asp 83
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Normal and ALS proteins Front Back
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References - Background pdb.org http://web.alsa.org/site/PageServer?pagename=ALSA_SOD1 http://www.ncbi.nlm.nih.gov/pubmed/12218958 http://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral- sclerosis/basics/definition/con-20024397 www.intechopen.com/books/current-advances-in-amyotrophic-lateral-sclerosis/superoxide- dismutase-and-oxidative-stress-in-amyotrophic-lateral-sclerosis https://alsrideforlife.org/support-us/ http://www.chem.utoronto.ca/coursenotes/GTM/Tours/sod/index.htm
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Reference - Structure http://bioinformatics.org/firstglance/fgij/ http://www.cathdb.info/ http://bioinf.cs.ucl.ac.uk/psipred/result/a47e849a-7986-11e4-8659-00163e110593 http://mordred.bioc.cam.ac.uk/~rapper/rampage2.php http://phobius.sbc.su.se/cgi-bin/predict.pl http://www.ch.embnet.org/cgi-bin/TMPRED_form_parser http://www.enzim.hu/hmmtop/server/hmmtop.cgi http://cello.life.nctu.edu.tw/cgi/main.cgi http://health-innovations.org/2014/10/15/scientists-link-als-progression-to-increased- protein-instability/ http://www.rcsb.org/pdb/explore/biologyAndChemistry.do?structureId=1PU0&bionumber=1
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