Acylation of Lens Proteins

晶状体蛋白的酰化

• 批准号: 9765327
• 负责人: Ram H Nagaraj
• 金额: $ 39.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765327
• 关键词: Acetyl Coenzyme A; Acetylation; Acyl Coenzyme A; Acylation; Adopted; Advanced Glycosylation End Products; Age; Aging; Amino Acids; Biochemical; Biochemical Reaction; Blindness; Cataract; Cells; Chemicals; Crystallins; Cysteine; Data; Exhibits; Human; In Vitro; Lead; Lipids; Lysine; Malonyl Coenzyme A; Measures; Mediating; Modification; Molecular Chaperones; Mutation; N acylation; Oxides; Pathway interactions; Pattern; Post-Translational Protein Processing; Presbyopia; Proteins; Reaction; Sirtuins; Site; Solubility; Structure; Testing; Tissues; Transferase; Translating; Visual impairment; acyl group; age effect; age related; aged; alpha-Crystallins; amino group; base; case-based; chemical reaction; experimental study; glycation; improved; lens; lens transparency; novel therapeutics; prevent; propionyl-coenzyme A; protein crosslink; protein structure function; resilience; succinyl-coenzyme A; therapy development; water solubility

N-acylation of cytosolic proteins is a common occurrence in tissues, and it regulates protein structure and function. The major N-acylation types in cells are acetylation, propionylation, succinylation and malonylation, which are initiated by the enzymatic or non-enzymatic transfer of acetyl CoA, propionyl CoA, succinyl CoA and malonyl CoA to lysine residues, respectively. Lens proteins are long lived with little or no turnover, and thus, post-translational modifications (PTMs) accumulate with age. The lack of enzymatically active proteins, particularly in the core of the lens, prohibits the reversal of PTMs. Thus, if deacylases are weak in the lens, acylation is mostly a one-way reaction that leads to permanent modifications of lens proteins, which appears to be the case (based on our preliminary data). The effects of acylation on lens proteins remain largely unknown. As shown in our previous study, the acetylation makes α-crystallin a better chaperone. In addition, our preliminary data show that lens proteins are also propionylated, succinylated and malonylated and that acetylation and succinylation increase the thermal stability and solubility of the proteins. Thus, we hypothesize that acylation of lens proteins is a beneficial PTM that helps maintain the chaperone activity of α- crystallin as well as the stability and solubility of lens proteins during aging. We will test this hypothesis in three aims. In Aim 1, we will determine the major acylation sites in human lens α-crystallin by mass spectrometric analyses and determine the effect of age on these modifications. In Aim 2, we will determine effects of acylation on the structure and function of α-crystallin. In Aim 3, we will evaluate the effects of acylation on the stability and solubility of lens proteins and determine whether acylation can be used to improve the compromised resilience of aged human lenses.

胞质蛋白的n -酰化在组织中很常见，它调节着蛋白质的结构和功能