Amyotrophic Lateral Sclerosis andSuperoxide Dimutase 1 (SOD1)

Iasson Yi

CHEM 4700

ALS

• Lou Gehrig’s Disease• Progressive neurodegenerative disease• Affects nerve cells in the brain and spinal cord• Motor neurons

ALS - Symptoms

• Muscle weakness• Twitching (fasciculation) and cramping• Shortness of breath, difficulty in breathing and

swallowing

• Ice bucket challenge

https://alsrideforlife.org/support-us/

ALS - Genetics

• Chromosome 21 – Gene SOD1• Many point mutations• Mutations in protein regions• Influence architectural integrity

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/)

SOD 1

• Superoxide Dimustase, Cu, Zn (aka SOD1)• Oxidoreductase

• CATH Superfamily 2.60.40.200• Functional family– Superoxide dismutase – like domain

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

General view

Protein characteristics• 10 chains• 153 amino acids per chain• Cu+ ligand• Zn2+ ligand• SO4

2- residues

• X-ray diffraction• Resolution: 2.40 angstroms

Secondary structure

Secondary structure• 3 alpha helices (9%)• 9 beta strands

(37.7%)• 53.3% neither

Motifs• Beta hairpins• Beta meander

Motifs• Beta barrel?

Disulfide bond

Active site - Ligands contacts• Cu ligand:– His 46– His 48– His 63– His 120

• Zn ligand– His 63– His 71– His 80– Asp 83

Active site – electrostatic loop – zinc loop

http://health-innovations.org/2014/10/15/scientists-link-als-progression-to-increased-protein-instability/

ALS – Secondary structure• 1 alpha helix

(3.3%)• 8 beta strands

(30.7%)• 66% neither

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

Normal and ALS proteins• Front • Back

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

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