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The role of isoaspartate in fibrillation and its prevention by Protein-L-isoaspartyl methyltransferase.
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2019-11-28 , DOI: 10.1016/j.bbagen.2019.129500 Tanaya Chatterjee 1 , Gaurav Das 2 , Barun K Chatterjee 3 , Jesmita Dhar 4 , Surajit Ghosh 2 , Pinak Chakrabarti 5
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2019-11-28 , DOI: 10.1016/j.bbagen.2019.129500 Tanaya Chatterjee 1 , Gaurav Das 2 , Barun K Chatterjee 3 , Jesmita Dhar 4 , Surajit Ghosh 2 , Pinak Chakrabarti 5
Affiliation
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BACKGROUND
Isomerization of aspartate to isoaspartate (isoAsp) on aging causes protein damage and malfunction. Protein-L-isoaspartyl methyltransferase (PIMT) performs a neuroprotective role by repairing such residues. A hexapeptide, Val-Tyr-Pro-(isoAsp)-His-Ala (VA6), a substrate of PIMT, is shown to form fibrils, while the normal Asp-containing peptide does not. Considering the role of PIMT against epileptic seizure, the combined effect of PIMT and two antiepileptic drugs (AEDs) (valproic acid and stiripentol) was investigated for anti-fibrillation activity.
METHODS
Structural/functional modulations due to the binding of AEDs to PIMT were investigated using biophysical techniques. Thioflavin T (ThT) fluorescence assay and microscopic methods were employed to study fibril formation by VA6. In vitro experiments with PC12 cells were carried out with PIMT/AEDs.
RESULTS
ThT assay indicated reduction of fibrillation of VA6 by PIMT. AEDs stabilize PIMT, bind close to the cofactor binding site, possibly exerting allosteric effect, increase the enzymatic activity, and anti-fibrillation efficacy. Furthermore, Aβ42, implicated in Alzheimer's disease, undergoes β-sheet to α-helix transition in presence of PIMT. Studies with PC12 derived neurons showed that PIMT and PIMT/AEDs exerted neuroprotective effect against anti-NGF induced neurotoxicity. This was further validated against neurotoxicity induced by Aβ42 in primary rat cortical neurons.
CONCLUSIONS
The study provides a new perspective to the role isoAsp in protein fibrillation, PIMT in its prevention and AEDs in enhancing the activity of the enzyme.
GENERAL SIGNIFICANCE
IsoAsp, with an additional C atom in the main-chain of polypeptide chain, may make it more susceptible to fibrillation. PIMT alone, or in association with AEDs prevents this.
中文翻译：
异天冬氨酸在原纤维形成中的作用及其蛋白L-异天冬氨酰甲基转移酶的预防作用。
背景技术随着时间的推移，天冬氨酸异构化为异天冬氨酸（isoAsp）会引起蛋白质损伤和功能障碍。蛋白质L-异天冬氨酰甲基转移酶（PIMT）通过修复此类残基来发挥神经保护作用。六肽Val-Tyr-Pro-（isoAsp）-His-Ala（VA6）（PIMT的底物）显示会形成原纤维，而正常的含Asp肽则不会。考虑到PIMT对癫痫发作的作用，研究了PIMT和两种抗癫痫药（AEDs）（丙戊酸和替比汀）的联合抗纤颤活性。方法使用生物物理技术研究了由于AED与PIMT结合而引起的结构/功能调节。硫黄素T（ThT）荧光测定法和显微方法用于研究VA6形成的原纤维。用PIMT / AED对PC12细胞进行体外实验。结果ThT分析表明PIMT可减少VA6的原纤化。AED稳定PIMT，在辅因子结合位点附近结合，可能发挥变构作用，增加酶活性和抗原纤维形成作用。此外，牵涉阿尔茨海默氏病的Aβ42在PIMT的作用下经历了从β折叠到α螺旋的转变。对PC12衍生神经元的研究表明，PIMT和PIMT / AED对抗NGF诱导的神经毒性具有神经保护作用。进一步验证了它对抗由Aβ42诱导的原代大鼠皮层神经元的神经毒性。结论该研究为isoAsp在蛋白原纤化中的作用，PIMT在其预防中的作用以及AED在增强酶活性中的作用提供了新的视角。一般意义IsoAsp 在多肽链的主链中带有一个额外的C原子，可能使其更易于原纤化。单独使用PIMT或与AED结合使用都可以避免这种情况。
更新日期：2019-11-28
中文翻译：
异天冬氨酸在原纤维形成中的作用及其蛋白L-异天冬氨酰甲基转移酶的预防作用。
背景技术随着时间的推移，天冬氨酸异构化为异天冬氨酸（isoAsp）会引起蛋白质损伤和功能障碍。蛋白质L-异天冬氨酰甲基转移酶（PIMT）通过修复此类残基来发挥神经保护作用。六肽Val-Tyr-Pro-（isoAsp）-His-Ala（VA6）（PIMT的底物）显示会形成原纤维，而正常的含Asp肽则不会。考虑到PIMT对癫痫发作的作用，研究了PIMT和两种抗癫痫药（AEDs）（丙戊酸和替比汀）的联合抗纤颤活性。方法使用生物物理技术研究了由于AED与PIMT结合而引起的结构/功能调节。硫黄素T（ThT）荧光测定法和显微方法用于研究VA6形成的原纤维。用PIMT / AED对PC12细胞进行体外实验。结果ThT分析表明PIMT可减少VA6的原纤化。AED稳定PIMT，在辅因子结合位点附近结合，可能发挥变构作用，增加酶活性和抗原纤维形成作用。此外，牵涉阿尔茨海默氏病的Aβ42在PIMT的作用下经历了从β折叠到α螺旋的转变。对PC12衍生神经元的研究表明，PIMT和PIMT / AED对抗NGF诱导的神经毒性具有神经保护作用。进一步验证了它对抗由Aβ42诱导的原代大鼠皮层神经元的神经毒性。结论该研究为isoAsp在蛋白原纤化中的作用，PIMT在其预防中的作用以及AED在增强酶活性中的作用提供了新的视角。一般意义IsoAsp 在多肽链的主链中带有一个额外的C原子，可能使其更易于原纤化。单独使用PIMT或与AED结合使用都可以避免这种情况。
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