The Cost of Long Catalytic Loops in Folding and Stability of the ALS-Associated Protein SOD1

Fan Yang, Huabing Wang, Derek T. Logan, Xin Mu, Jens Danielsson, Mikael Oliveberg

Research output: Contribution to journalArticlepeer-review


A conspicuous feature of the amyotrophic lateral sclerosis (ALS)-associated protein SOD1 is that its maturation into a functional enzyme relies on local folding of two disordered loops into a catalytic subdomain. To drive the disorder-to-order transition, the protein employs a single Zn2+ ion. The question is then if the entropic penalty of maintaining such disordered loops in the immature apoSOD1 monomer is large enough to explain its unusually low stability, slow folding, and pathological aggregation in ALS. To find out, we determined the effects of systematically altering the SOD1-loop lengths by protein redesign. The results show that the loops destabilize the apoSOD1 monomer by kcal/mol, rendering the protein marginally stable and accounting for its aggregation behavior. Yet the effect on the global folding kinetics remains much smaller with a transition-state destabilization of <1 kcal/mol. Notably, this 1/3 transition-state to folded-state stability ratio provides a clear-cut example of the enigmatic disagreement between the Leffler α value from loop-length alterations (typically 1/3) and the "standard" reaction coordinates based on solvent perturbations (typically >2/3). Reconciling the issue, we demonstrate that the disagreement disappears when accounting for the progressive loop shortening that occurs along the folding pathway. The approach assumes a consistent Flory loop entropy scaling factor of c = 1.48 for both equilibrium and kinetic data and has the added benefit of verifying the tertiary interactions of the folding nucleus as determined by phi-value analysis. Thus, SOD1 not only represents a case where evolution of key catalytic function has come with the drawback of a destabilized apo state but also stands out as a well-suited model system for exploring the physicochemical details of protein self-organization.

Original languageEnglish
Pages (from-to)16570-16579
Number of pages10
JournalJournal of the American Chemical Society
Issue number48
Publication statusPublished - 2018

Subject classification (UKÄ)

  • Biochemistry and Molecular Biology


Dive into the research topics of 'The Cost of Long Catalytic Loops in Folding and Stability of the ALS-Associated Protein SOD1'. Together they form a unique fingerprint.

Cite this