Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, Jülich, Germany.
Institut für Physikalische Biologie, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Transl Psychiatry. 2021 Dec 17;11(1):639. doi: 10.1038/s41398-021-01765-1.
Chronic mental illnesses (CMIs) pose a significant challenge to global health due to their complex and poorly understood etiologies and hence, absence of causal therapies. Research of the past two decades has revealed dysfunction of the disrupted in schizophrenia 1 (DISC1) protein as a predisposing factor involved in several psychiatric disorders. DISC1 is a multifaceted protein that serves myriads of functions in mammalian cells, for instance, influencing neuronal development and synapse maintenance. It serves as a scaffold hub forming complexes with a variety (~300) of partners that constitute its interactome. Herein, using combinations of structural and biophysical tools, we demonstrate that the C-region of the DISC1 protein is highly polymorphic, with important consequences for its physiological role. Results from solid-state NMR spectroscopy and electron microscopy indicate that the protein not only forms symmetric oligomers but also gives rise to fibrils closely resembling those found in certain established amyloid proteinopathies. Furthermore, its aggregation as studied by isothermal titration calorimetry (ITC) is an exergonic process, involving a negative enthalpy change that drives the formation of oligomeric (presumably tetrameric) species as well as β-fibrils. We have been able to narrow down the β-core region participating in fibrillization to residues 716-761 of full-length human DISC1. This region is absent in the DISC1 splice variant, resulting in reduced association with proteins from the dynein motor complex, viz., NDE-like 1 (NDEL1) and lissencephaly 1 (LIS1), which are crucial during mitosis. By employing surface plasmon resonance, we show that the oligomeric DISC1 C-region has an increased affinity and shows cooperativity in binding to LIS1 and NDEL1, in contrast to the noncooperative binding mode exhibited by the monomeric version. Based on the derived structural models, we propose that the association between the binding partners involves two neighboring subunits of DISC1 C-region oligomers. Altogether, our findings highlight the significance of the DISC1 C-region as a crucial factor governing the balance between its physiological role as a multifunctional scaffold protein and aggregation-related aberrations with potential significance for disease.
慢性精神疾病（CMI）由于其复杂且尚未被充分理解的病因，以及缺乏因果治疗方法，对全球健康构成了重大挑战。过去二十年的研究表明， disrupted in schizophrenia 1（DISC1）蛋白的功能障碍是涉及多种精神疾病的易患因素。DISC1 是一种多功能蛋白，在哺乳动物细胞中发挥着多种功能，例如影响神经元发育和突触维持。它作为一个支架枢纽，与构成其相互作用组的约 300 种不同的伙伴形成复合物。在此，我们使用结构和生物物理工具的组合，证明 DISC1 蛋白的 C 区高度多态，对其生理功能有重要影响。固态 NMR 光谱和电子显微镜的结果表明，该蛋白不仅形成对称的寡聚物，还产生类似于某些已建立的淀粉样蛋白病理中发现的纤维。此外，等温滴定量热法（ITC）研究表明其聚集是一个放能过程，涉及负焓变化，驱动寡聚体（可能是四聚体）和β-纤维的形成。我们已经能够将参与纤维化的β核心区域缩小到全长人 DISC1 的 716-761 个残基。该区域不存在于 DISC1 剪接变体中，导致与动力蛋白复合物的蛋白质的结合减少，即，NDE 样蛋白 1（NDEL1）和无脑回畸形蛋白 1（LIS1），这在有丝分裂过程中是至关重要的。通过表面等离子体共振，我们表明寡聚 DISC1 C 区在与 LIS1 和 NDEL1 结合时具有更高的亲和力和协同性，与单体版本表现出的非协同结合模式相反。基于推导的结构模型，我们提出结合伴侣之间的相互作用涉及 DISC1 C 区寡聚体的两个相邻亚基。总的来说，我们的研究结果强调了 DISC1 C 区作为调节其作为多功能支架蛋白的生理作用与聚集相关异常之间平衡的关键因素的重要性，这对疾病具有潜在意义。
