Varricchio Lilian, Falchi Mario, Dall'Ora Massimiliano, De Benedittis Caterina, Ruggeri Alessandra, Uversky Vladimir N, Migliaccio Anna Rita
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
National HIV/AIDS Center, Istituto Superiore Sanità, Rome, Italy.
Front Cell Dev Biol. 2017 Nov 23;5:96. doi: 10.3389/fcell.2017.00096. eCollection 2017.
Calreticulin is a Ca-binding chaperone protein, which resides mainly in the endoplasmic reticulum but also found in other cellular compartments including the plasma membrane. In addition to Ca, calreticulin binds and regulates almost all proteins and most of the mRNAs deciding their intracellular fate. The potential functions of calreticulin are so numerous that identification of all of them is becoming a nightmare. Still the recent discovery that patients affected by the Philadelphia-negative myeloproliferative disorders essential thrombocytemia or primary myelofibrosis not harboring JAK2 mutations carry instead calreticulin mutations disrupting its C-terminal domain has highlighted the clinical need to gain a deeper understanding of the biological activity of this protein. However, by contrast with other proteins, such as enzymes or transcription factors, the biological functions of which are strictly defined by a stable spatial structure imprinted by their amino acid sequence, calreticulin contains intrinsically disordered regions, the structure of which represents a highly dynamic conformational ensemble characterized by constant changes between several metastable conformations in response to a variety of environmental cues. This article will illustrate the Theory of calreticulin as an intrinsically disordered protein and discuss the Hypothesis that the dynamic conformational changes to which calreticulin may be subjected by environmental cues, by promoting or restricting the exposure of its active sites, may affect its function under normal and pathological conditions.
钙网蛋白是一种钙结合伴侣蛋白，主要存在于内质网中，但也存在于包括质膜在内的其他细胞区室中。除了钙之外，钙网蛋白还能结合并调节几乎所有蛋白质和大多数信使核糖核酸，决定它们在细胞内的命运。钙网蛋白的潜在功能非常之多，以至于识别其所有功能正成为一场噩梦。不过，最近有一项发现，即患有费城染色体阴性骨髓增殖性疾病（原发性血小板增多症或原发性骨髓纤维化）且不携带JAK2突变的患者，反而携带钙网蛋白突变，这些突变破坏了其C末端结构域，这凸显了临床上更深入了解该蛋白生物学活性的必要性。然而，与其他蛋白质（如酶或转录因子）不同，它们的生物学功能由其氨基酸序列所赋予的稳定空间结构严格定义，而钙网蛋白含有内在无序区域，其结构代表了一种高度动态的构象集合体，其特征是响应各种环境线索，在几种亚稳态构象之间不断变化。本文将阐述钙网蛋白作为一种内在无序蛋白的理论，并讨论这样一种假说，即环境线索可能使钙网蛋白发生动态构象变化，通过促进或限制其活性位点的暴露，可能会影响其在正常和病理条件下的功能。
