Amyotrophic Lateral Sclerosis and Superoxide 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

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 ( Areas of research – miRNA ( – Stem cell-derived motor neurons (

SOD 1 Superoxide Dimustase, Cu, Zn (aka SOD1) Oxidoreductase CATH Superfamily Functional family – Superoxide dismutase – like domain

SOD1 - Mechanism Converts harmful superoxide radicals to oxygen and hydrogen peroxide sclerosis/superoxide-dismutase-and-oxidative-stress-in-amyotrophic- lateral-sclerosis

General view

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

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 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 sclerosis/basics/definition/con dismutase-and-oxidative-stress-in-amyotrophic-lateral-sclerosis

Reference - Structure protein-instability/