Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, S-751 24 Uppsala, Sweden.
Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2325-9. doi: 10.1073/pnas.1114740109. Epub 2012 Feb 2.
BRICHOS domains are encoded in > 30 human genes, which are associated with cancer, neurodegeneration, and interstitial lung disease (ILD). The BRICHOS domain from lung surfactant protein C proprotein (proSP-C) is required for membrane insertion of SP-C and has anti-amyloid activity in vitro. Here, we report the 2.1 Å crystal structure of the human proSP-C BRICHOS domain, which, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry, reveals how BRICHOS domains may mediate chaperone activity. Observation of amyloid deposits composed of mature SP-C in lung tissue samples from ILD patients with mutations in the BRICHOS domain or in its peptide-binding linker region supports the in vivo relevance of the proposed mechanism. The results indicate that ILD mutations interfering with proSP-C BRICHOS activity cause amyloid disease secondary to intramolecular chaperone malfunction.
BRICHOS 结构域存在于超过 30 个人类基因中，与癌症、神经退行性疾病和间质性肺病（ILD）有关。肺表面活性蛋白 C 前蛋白（proSP-C）中的 BRICHOS 结构域对于 SP-C 的膜插入是必需的，并且在体外具有抗淀粉样活性。在这里，我们报告了人 proSP-C BRICHOS 结构域的 2.1 Å 晶体结构，结合分子动力学模拟和氢氘交换质谱，揭示了 BRICHOS 结构域如何介导伴侣活性。在 BRICHOS 结构域或其肽结合接头区域发生突变的ILD 患者的肺组织样本中观察到由成熟 SP-C 组成的淀粉样沉积物，支持了所提出机制的体内相关性。结果表明，干扰 proSP-C BRICHOS 活性的 ILD 突变导致淀粉样疾病继发于分子内伴侣功能障碍。
