amyotrophic lateral sclerosis and superoxide dimutase 1 (sod1) iasson yi chem 4700
TRANSCRIPT
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Amyotrophic Lateral Sclerosis andSuperoxide 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/)
• Areas of research– miRNA (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781640/)
– Stem cell-derived motor neurons (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• Zn2+ ligand• SO4
2- residues
• X-ray diffraction• Resolution: 2.40 angstroms
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Secondary structure
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Secondary structure• 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