Factors Modulating the Interaction of Huntingtin with Lipid Membranes: Implications for Huntington's Disease
| Autor: | Pranav Jain, Maxmore Chaibva, Xiang Gao, Olivia Sarver, Justin Legleiter, Stephen J. Valentine, James R. Arndt |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
chemistry.chemical_classification
congenital hereditary and neonatal diseases and abnormalities Huntingtin Cholesterol Vesicle Biophysics Fibril medicine.disease nervous system diseases Amino acid chemistry.chemical_compound Membrane nervous system chemistry Huntington's disease Biochemistry Acetylation mental disorders medicine |
| Zdroj: | Biophysical Journal. 110(3):358a-359a |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2015.11.1933 |
| Popis: | Huntington disease (HD) is a genetic neurodegenerative disease caused by an expanded polyglutamine (polyQ) domain in the first exon of the huntingtin (Htt) protein. This polyQ expansions leads directly to the formation of proteinaceous aggregates including oligomers and fibrils. Htt interacts with a variety of membraneous structures within the cell, and the first seventeen amino acids (Nt17) of Htt, which directly flanks the polyQ domain, is an amphiphathic α-helix (AH) lipid-binding domain. Here, the role that lipid/htt interactions play in aggregation was investigated with a specific emphasis on the role of Nt17 acetylation and membrane cholesterol content. N-terminal acetylation of htt has been implicated in the etiology of HD, and cholesterol homeostasis is altered in HD. A variety of aggregation assays, lipid binding assays, mass spectrometry, and atomic force microscopy were used. The model membrane systems were vesicles and supported bilayers comprised of total brain lipid extract (TBLE), and these were exposed to a variety of purified or synthetic peptides modeled after htt exon1. Acetylation of htt was achieved using a selective covalent label sulfo-N-hydroxysuccinimide (NHSA). Acetylation retarded fibril formation, promoted the formation of larger globular aggregates, and altered htt's ability to bind lipid membranes. Exogenous cholesterol was incorporated into our model TBLE membranes. As cholesterol content increased, morphological and mechanical changes in the bilayer associated with exposure to Htt were drastically altered. Collectively, these observations suggest that the acetylation and cholesterol content of bilayers play a critical role in htt binding to and aggregation on lipid membranes. |
| Databáze: | OpenAIRE |
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