Class 1 cytokine receptors (C1CRs) are single-pass transmembrane proteins responsible for transmitting signals between the outside and the inside of cells. Remarkably, they orchestrate key biological processes such as proliferation, differentiation, immunity and growth through long disordered intracellular domains (ICDs), but without having intrinsic kinase activity. Despite these key roles, their characteristics remain rudimentarily understood. The current paper asks the question of why disorder has evolved to govern signaling of C1CRs by reviewing the literature in combination with new sequence and biophysical analyses of chain properties across the family. We uncover that the C1CR-ICDs are fully disordered and brimming with SLiMs. Many of these short linear motifs (SLiMs) are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CR-ICDs have unique properties that distinguish them from most IDPs and we forward the perception that the C1CR-ICDs are far from simple strings with constitutively bound kinases. Rather, they carry both organizational and operational features left uncovered within their disorder, including mechanisms and complexities of regulatory functions. Critically, the understanding of the fascinating ability of these long, completely disordered chains to orchestrate complex cellular signaling pathways is still in its infancy, and we urge a perceptional shift away from the current simplistic view towards uncovering their full functionalities and potential.

中文翻译：

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1 类细胞因子受体结构紊乱对信号的协调。

1 类细胞因子受体 (C1CR) 是单次跨膜蛋白，负责在细胞内外传递信号。值得注意的是，它们通过长无序的细胞内结构域 (ICD) 协调关键的生物过程，如增殖、分化、免疫和生长，但没有内在的激酶活性。尽管有这些关键作用，但他们的特征仍然基本被理解。目前的论文通过回顾文献，结合新序列和对整个家族链特性的生物物理分析，提出了为什么紊乱已经演变为控制 C1CR 信号的问题。我们发现 C1CR-ICD 是完全无序的，并且充满了 SLiM。许多这些短线性基序（SLiMs）是重叠的，共同表示相互作用的复杂调节，包括通过异构体进行网络重新布线。C1CR-ICDs 具有独特的特性，将它们与大多数 IDP 区分开来，我们认为 C1CR-ICDs 远不是具有组成型结合激酶的简单字符串。相反，它们具有在其紊乱中未被发现的组织和操作特征，包括监管功能的机制和复杂性。至关重要的是，对这些长而完全无序的链协调复杂细胞信号通路的迷人能力的理解仍处于起步阶段，我们敦促从当前的简单化观点转向揭示其全部功能和潜力的认知转变。C1CR-ICDs 具有独特的特性，将它们与大多数 IDP 区分开来，我们认为 C1CR-ICDs 远不是具有组成型结合激酶的简单字符串。相反，它们具有在其紊乱中未被发现的组织和操作特征，包括监管功能的机制和复杂性。至关重要的是，对这些长而完全无序的链协调复杂细胞信号通路的迷人能力的理解仍处于起步阶段，我们敦促从当前的简单化观点转向揭示其全部功能和潜力的认知转变。C1CR-ICDs 具有独特的特性，将它们与大多数 IDP 区分开来，我们认为 C1CR-ICDs 远不是具有组成型结合激酶的简单字符串。相反，它们具有在其紊乱中未被发现的组织和操作特征，包括监管功能的机制和复杂性。至关重要的是，对这些长而完全无序的链协调复杂细胞信号通路的迷人能力的理解仍处于起步阶段，我们敦促从当前的简单化观点转向揭示其全部功能和潜力的认知转变。包括监管功能的机制和复杂性。至关重要的是，对这些长而完全无序的链协调复杂细胞信号通路的迷人能力的理解仍处于起步阶段，我们敦促从当前的简单化观点转向揭示其全部功能和潜力的认知转变。包括监管功能的机制和复杂性。至关重要的是，对这些长而完全无序的链协调复杂细胞信号通路的迷人能力的理解仍处于起步阶段，我们敦促从当前的简单化观点转向揭示其全部功能和潜力的认知转变。