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  • 1.
    Danielsson, Jens
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mu, Xin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lang, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wang, Huabing
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Binolfi, Andres
    Theillet, Franois-Xavier
    Bekei, Beata
    Logan, Derek T.
    Selenko, Philipp
    Wennerström, Håkan
    Oliveberg, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Thermodynamics of protein destabilization in live cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 40, p. 12402-12407Article in journal (Refereed)
    Abstract [en]

    Although protein folding and stability have been well explored under simplified conditions in vitro, it is yet unclear how these basic self-organization events are modulated by the crowded interior of live cells. To find out, we use here in-cell NMR to follow at atomic resolution the thermal unfolding of a beta-barrel protein inside mammalian and bacterial cells. Challenging the view from in vitro crowding effects, we find that the cells destabilize the protein at 37 degrees C but with a conspicuous twist: While the melting temperature goes down the cold unfolding moves into the physiological regime, coupled to an augmented heat-capacity change. The effect seems induced by transient, sequence-specific, interactions with the cellular components, acting preferentially on the unfolded ensemble. This points to a model where the in vivo influence on protein behavior is case specific, determined by the individual protein's interplay with the functionally optimized interaction landscape of the cellular interior.

  • 2.
    Wang, Huabing
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Lang, Lisa
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Logan, Derek T.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Oliveberg, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Tricking a Protein To Swap Strands2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 48, p. 15571-15579Article in journal (Refereed)
    Abstract [en]

    Despite continuing interest in partly unfolded proteins as precursors for aggregation and adverse gain-of-function in human disease, there is yet little known about the local transitions of native structures that possibly lead to such intermediate states. To target this problem, we present here a protein-design strategy that allows real-time detection of rupture and swapping of complete secondary-structure elements in globular proteins molecular events that have previously been inaccessible experimental analysis. The approach is applied to the dynamic beta-barrel of SOD1, associated with pathologic aggregation in the neurodegenerative disease ALS. Data show that rupture and re-insertion of individual beta-strands do not take place locally but require the SOD1 barrel to unfold globally. The finding questions the very existence of partly unfolded intermediates in the SOD1 aggregation process and presents new clues to the mechanism by which hydrogen bonding maintains global structural integrity.

  • 3.
    Yang, Fan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wang, Huabing
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Logan, Derek T.
    Mu, Xin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Danielsson, Jens
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Oliveberg, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The Cost of Long Catalytic Loops in Folding and Stability of the ALS-Associated Protein SOD12018In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 48, p. 16570-16579Article in journal (Refereed)
    Abstract [en]

    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 similar to 3 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 alpha 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.

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