发表机构
Institute of Engineering in Medicine University of California, San Diego（加州大学圣地亚哥分校工程医学院）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
该研究通过HPA数据揭示PPI级联分子架构，阐明EMC组装机制，并发现突触蛋白隔离导致神经退行性变，恢复蛋白可用性可修复损伤。
AI 中文摘要
在结合转座元件种子DNA后，起始转录因子通过迭代参与蛋白-蛋白相互作用（PPI）级联反应，并创建细胞类型特异性的蛋白二聚体池，从而激活内源性多蛋白复合物（EMC）的混合组装途径（HAP）。在此，我们在人类蛋白质图谱（HPA）中记录的154种人类细胞类型的细胞类型特异性细胞内蛋白单体池背景下，阐明了PPI级联反应组分的分子特征和推断的生物学功能。在HPA的细胞内蛋白质组背景下，记录了4个PPI级联反应家族分子架构和功能表现的以下关键特征：a）普遍表达和均衡代表；c）普遍可用性和参与；d）EMC的组成性（不变）和细胞类型特异性组装谱。PPI级联的生物学相关性通过跨人体HPA的细胞类型分辨多蛋白复合物参与分析得到证明，该分析无需监督即可忠实恢复EMC的内在谱系结构和谱系特异性主调控多蛋白组装。PPI级联组分在154种人类细胞的蛋白质组可用性背景下具有生成51,830个蛋白二聚体的能力。当前分析揭示了蛋白病蛋白持续存在可能通过隔离44种突触蛋白而对PPI级联性能造成损害的关键影响。突触蛋白的隔离撤除了突触的结构-功能组分，提示了一种促进神经退行性变发病机制的机制。相反，恢复特定突触结构蛋白的可用性似乎能恢复化学计量比并恢复丢失的突触蛋白二聚体组装。
英文摘要
Upon binding to transposable elements seeded DNA, initiator transcription factors are poised to activate the hybrid assembly pathways (HAP) of endogenous multiprotein complexes (EMC) by iteratively engaging protein-protein interaction (PPI) cascade and creating cell type-specific pools of protein dimers. Here, molecular features and inferred biological functions of PPI cascade constituents were elucidated within the context of cell type-specific intracellular protein monomer pools documented in the Human Protein Atlas (HPA) of 154 human cell types. The following key features of the molecular architecture and functional performance of the 4 families of PPI cascade constituents were documented within the HPA contexts of intracellular proteomes: a) the ubiquitous expression and balanced representation; c) the universal availability and engagements; d) constitutive {invariant) and cell type-specific assembly profiles of EMCs. The biological relevance of the PPI cascades is demonstrated by cell-type-resolved multiprotein complex-engagement analysis across the HPA of human body, which faithfully recovers without supervision the intrinsic lineage structures of EMCs and lineage-specific master-regulator multiprotein assemblies. PPI cascade constituents have the capacity to generate 51,830 protein dimers within the proteome availability contexts of 154 types of human cells. Present analyses revealed critical impacts of the persistence of proteinopathy proteins that may cause the damage to the PPI cascade performance by sequestering 44 synaptic proteins. The sequestration of synaptic proteins withdraws structural-functional components of synapses suggesting a mechanism contributing to the pathogenesis of neurodegeneration. Conversely, reconstitution of availability of defined synaptic structural proteins appears to restore stoichiometry and recovers the lost assembly of synaptic protein dimers.
Comments24 pages, 9 figures
