To Fold or to Misfold: What is the Problem? (Molecular Origami) - PowerPoint PPT Presentation

To Fold or to Misfold: What is the Problem? (Molecular Origami) Sheena E Radford Astbury Centre for Structural Molecular Biology University of Leeds

Proteins Fold to Amazingly Complex Structures! The Protein Folding Problem: How is the correct fold .. from only their amino acid sequences sought and found and errors avoided or corrected?

Nature’s Origami: Cracking the Folding Code Chris Anfinsen Nobel Prize 1972

Proteins Fold to Amazingly Complex Structures! It is an amazing feat of evolution that proteins fold and assemble in the cell rapidly and efficiently. Diseases associated with protein misfolding, whilst rare in terms of .. from only their amino acid sequences protein sequences, are a major threat to human health today

Diseases of Protein Misfolding: a Major Threat Type II diabetes Cost in $Bn • More than 50 known protein aggregation-based diseases. • Includes two of the most prevalent and life-threatening diseases of the developed world – Alzheimer’s Alzheimer’s disease disease and Type II diabetes. Cost in $Bn • Enormous economic and social burden. • Diagnosis/prognosis difficult, therapies either poor or not Sources: CDC; Projection of the year 2050 burden currently available of diabetes in the US population; Alzheimer’s Study Group, National Alzheimer’s Strategic Plan, NIH.

Amyloid Disorders: A Large Class of Diseases Machado Joseph Disease • ataxin 3 Alzheimer’s Disease • A β Parkinson’s Disease • α -synuclein Transmissible spongiform encephalopathy • Prion Cardiac amyloidosis • e.g. Immunoglobulin Medullary thyroid cancer light chain • Calcitonin Dialysis related amyloidosis Type II Diabetes • β 2 -microglobulin • Amylin/IAPP Light chain amyloidosis • Immunoglobulin light chain Neurodegeneration Atherosclerosis Systemic/ Localised Amyloidosis • Apolipoprotein A1 Pathogen Infectivity Cancer

How do proteins fold? How do proteins misfold? How does protein misfolding affect cells? Can we use structural molecular knowledge to combat disease?

Diseases of Protein Misfolding

Amyloid fibrils: Beautiful, Yet Deadly Structures Wasmer, Riek, Sawaya, Eisenberg et al. Meier et al . Sheynis, Radford et al. Saibil et al. Milanesi, Saibil, Radford et al. Jimenez, White, Saibil, Saibil et al . Radford et al.

Amyloid fibrils: Beautiful, Yet Deadly Structures Which sequence / structural /cellular factors promote folding versus aggregation ? What happens to tip the balance ? How can we use this knowledge to combat disease ?

Molecular Dissection of Amyloid Formation The goal is to determine the nature of the folding and aggregation landscapes in atomistic detail. Use biochemical, biophysical, cell biological, computational methods

β 2 -microglobulin: Dialysis Related Amyloidosis MHC c la ss I α 2 α 1 α 3 β 2 m β 2 m (T r inh 2002 1L DS) β 2 -microglobulin, essential for a myloid fibril (White , 2009) immunity, aggregates and causes disease (Nature SMB, 2002, 2006, Mol Cell 2011, 2014)

Molecular Dissection of Amyloid Formation Thomas Jahn Solving the folding pathway Isomerisation of only a SINGLE peptide bond initiates aggregation Fibril (Nature SMB, 2002, 2006, Mol Cell 2011)

Mass Spectrometry: Seeing Oligomers Native Mass Spectrometry: A new tool for screening and classifying amyloid inhibitors that target defined species (PNAS 2010, Nature Chem Biol, 2011) With Prof Alison Ashcroft (UoL)

NMR: Amyloid Formation in Atomic Detail Protein Folding Intermediates: Dangerous potentially infectious materials (Molecular Cell, 2014)

Nature’s Origami: Cracking the Folding Code Chris Anfinsen Nobel Prize 1972

Group Past and Present Friends, Colleagues Collaborators Funding Agencies (including BBSRC, MRC WT, ERC)