Browsing by Author "Hancu, Maria C."

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    Exploration of the hierarchical assembly space of collagen-like peptides beyond the triple helix
    (Springer Nature, 2024) Yu, Le Tracy; Kreutzberger, Mark A. B.; Bui, Thi H.; Hancu, Maria C.; Farsheed, Adam C.; Egelman, Edward H.; Hartgerink, Jeffrey D.; Bioengineering; Chemistry
    The de novo design of self-assembling peptides has garnered significant attention in scientific research. While alpha-helical assemblies have been extensively studied, exploration of polyproline type II helices, such as those found in collagen, remains relatively limited. In this study, we focus on understanding the sequence-structure relationship in hierarchical assemblies of collagen-like peptides, using defense collagen Surfactant Protein A as a model. By dissecting the sequence derived from Surfactant Protein A and synthesizing short collagen-like peptides, we successfully construct a discrete bundle of hollow triple helices. Amino acid substitution studies pinpoint hydrophobic and charged residues that are critical for oligomer formation. These insights guide the de novo design of collagen-like peptides, resulting in the formation of diverse quaternary structures, including discrete and heterogenous bundled oligomers, two-dimensional nanosheets, and pH-responsive nanoribbons. Our study represents a significant advancement in the understanding and harnessing of collagen higher-order assemblies beyond the triple helix.
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    Mitochondria-affecting small molecules ameliorate proteostasis defects associated with neurodegenerative diseases
    (Springer Nature, 2021) Tjahjono, Elissa; Pei, Jingqi; Revtovich, Alexey V.; Liu, Terri-Jeanne E.; Swadi, Alisha; Hancu, Maria C.; Tolar, Joe G.; Kirienko, Natalia V.
    Macroautophagic recycling of dysfunctional mitochondria, known as mitophagy, is essential for mitochondrial homeostasis and cell viability. Accumulation of defective mitochondria and impaired mitophagy have been widely implicated in many neurodegenerative diseases, and loss-of-function mutations of PINK1 and Parkin, two key regulators of mitophagy, are amongst the most common causes of heritable parkinsonism. This has led to the hypothesis that pharmacological stimulation of mitophagy may be a feasible approach to combat neurodegeneration. Toward this end, we screened ~ 45,000 small molecules using a high-throughput, whole-organism, phenotypic screen that monitored accumulation of PINK-1 protein, a key event in mitophagic activation, in a Caenorhabditis elegans strain carrying a Ppink-1::PINK-1::GFP reporter. We obtained eight hits that increased mitochondrial fragmentation and autophagosome formation. Several of the compounds also reduced ATP production, oxygen consumption, mitochondrial mass, and/or mitochondrial membrane potential. Importantly, we found that treatment with two compounds, which we named PS83 and PS106 (more commonly known as sertraline) reduced neurodegenerative disease phenotypes, including delaying paralysis in a C. elegans β-amyloid aggregation model in a PINK-1-dependent manner. This report presents a promising step toward the identification of compounds that will stimulate mitochondrial turnover.