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Abstract Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF^WT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF^D380A) and severe (OLF^I499F) disease variants aggregate differently, with rates comparable to OLF^WTin initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF^WTurea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. 

Abstract Sensing and responding to temperature is crucial in biology. The TRPV1 ion channel is a well-studied heat-sensing receptor that is also activated by vanilloid compounds, including capsaicin. Despite significant interest, the molecular underpinnings of thermosensing have remained elusive. The TRPV1 S1-S4 membrane domain couples chemical ligand binding to the pore domain during channel gating. Here we show that the S1-S4 domain also significantly contributes to thermosensing and couples to heat-activated gating. Evaluation of the isolated human TRPV1 S1-S4 domain by solution NMR, far-UV CD, and intrinsic fluorescence shows that this domain undergoes a non-denaturing temperature-dependent transition with a high thermosensitivity. Further NMR characterization of the temperature-dependent conformational changes suggests the contribution of the S1-S4 domain to thermosensing shares features with known coupling mechanisms between this domain with ligand and pH activation. Taken together, this study shows that the TRPV1 S1-S4 domain contributes to TRPV1 temperature-dependent activation. 

Abstract Abundant Li resources in the ocean are promising alternatives to refining ore, whose supplies are limited by the total amount and geopolitical imbalance of reserves in Earth's crust. Despite advances in Li⁺extraction using porous membranes, they require screening other cations on a large scale due to the lack in precise control of pore size and inborn defects. Herein, MoS₂nanoflakes on a multilayer graphene membrane (MFs‐on‐MGM) that possess ion channels comprising i) van der Waals interlayer gaps for optimal Li⁺extraction and ii) negatively charged vertical inlets for cation attraction, are reported. Ion transport measurements across the membrane reveal ≈6‐ and 13‐fold higher selectivity for Li⁺compared to Na⁺and Mg²⁺, respectively. Furthermore, continuous, stable Li⁺extraction from seawater is demonstrated by integrating the membrane into a H₂and Cl₂evolution system, enabling more than 10⁴‐fold decrease in the Na⁺concentration and near‐complete elimination of other cations.