German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
Department of Molecular Medicine, Morsani College of Medicine, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, 33613, USA.
Nat Commun. 2020 Nov 27;11(1):6046. doi: 10.1038/s41467-020-19844-0.
Catalysis of cis/trans isomerization of prolines is important for the activity and misfolding of intrinsically disordered proteins. Catalysis is achieved by peptidylprolyl isomerases, a superfamily of molecular chaperones. Here, we provide atomic insight into a tug-of-war between cis/trans isomerization and molecular chaperone activity. Catalysis of proline isomerization by cyclophilin A lowers the energy barrier for α-synuclein misfolding, while isomerase-binding to a separate, disease-associated protein region opposes aggregation. We further show that cis/trans isomerization outpowers the holding activity of cyclophilin A. Removal of the proline isomerization barrier through posttranslational truncation of α-synuclein reverses the action of the proline isomerase and turns it into a potent molecular chaperone that inhibits protein misfolding. The data reveal a conserved mechanism of dual functionality in cis/trans isomerases and define its molecular determinants acting on intrinsically disordered proteins.
脯氨酸顺/反异构化的催化对于无规卷曲蛋白质的活性和错误折叠至关重要。这种催化是由肽基脯氨酰顺反异构酶（peptidylprolyl isomerases）完成的，它是分子伴侣超家族的一员。在这里，我们提供了原子水平的见解，揭示了顺/反异构化和分子伴侣活性之间的拔河比赛。亲环素 A 催化脯氨酸异构化降低了α-突触核蛋白错误折叠的能垒，而异构酶与另一个与疾病相关的蛋白质区域结合则阻碍了聚集。我们进一步表明，顺/反异构化超过了亲环素 A 的结合活性。通过α-突触核蛋白的翻译后截断去除脯氨酸异构化障碍，逆转了脯氨酸异构酶的作用，使其成为一种有效的分子伴侣，抑制蛋白质错误折叠。这些数据揭示了顺/反异构酶的双重功能的保守机制，并定义了其作用于无规卷曲蛋白质的分子决定因素。
