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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco
Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill Zitzewitz, John Landers, Bruce Goode, Celia Schiffer, Daryl Bosco
Celia A. Schiffer
Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the …
Exploring The Role Of The Solvent In The Denaturation Of A Protein: A Molecular Dynamics Study Of The Dna Binding Domain Of The 434 Repressor, Celia Schiffer, Volker Dötsch, Kurt Wuthrich, Wilfred Van Gunsteren
Exploring The Role Of The Solvent In The Denaturation Of A Protein: A Molecular Dynamics Study Of The Dna Binding Domain Of The 434 Repressor, Celia Schiffer, Volker Dötsch, Kurt Wuthrich, Wilfred Van Gunsteren
Celia A. Schiffer
Molecular dynamics simulations of the DNA binding domain of 434 repressor are presented which aim at unraveling the role of solvent in protein denaturation. Four altered solvent models, each mimicking various possible aspects of the addition of a denaturant to the aqueous solvent, were used in the simulations to analyze their effects on the stability of the protein. The solvent was altered by selectively changing the Coulombic interaction between water and protein atoms and between different water molecules. The use of a modified solvent model has the advantage of mimicking the presence of denaturant without having denaturant molecules present in …