Dynamics of an intrinsically disordered protein reveal metastable conformations that potentially seed aggregation

Amyloid fibril deposits of the intrinsically disordered hIAPP peptide are found in 95% of type II diabetes patients, and the aggregation of this peptide is suggested to induce apoptotic cell-death in insulin-producing β-cells. Understanding the structure and dynamics of the hIAPP monomer in solution is thus important for understanding the nucleation of aggregatio…

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Hierarchical Nyström methods for constructing Markov state models for conformational dynamics

Markov state models (MSMs) have become a popular approach for investigating the conformational dynamics of proteins and other biomolecules. MSMs are typically built from numerous molecular dynamics simulations by dividing the sampled configurations into a large number of microstates based on geometric criteria. The resulting microstate model can then be coarse-gr…

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Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15

Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ(c)). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ(c) quaternary complex, IL-15 binds to IL-2Rβ and γ(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ(c) complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, a…

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