Melchior John T, Walker Ryan G, Cooke Allison L, Morris Jamie, Castleberry Mark, Thompson Thomas B, Jones Martin K, Song Hyun D, Rye Kerry-Anne, Oda Michael N, Sorci-Thomas Mary G, Thomas Michael J, Heinecke Jay W, Mei Xiaohu, Atkinson David, Segrest Jere P, Lund-Katz Sissel, Phillips Michael C, Davidson W Sean
Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio, USA.
Nat Struct Mol Biol. 2017 Dec;24(12):1093-1099. doi: 10.1038/nsmb.3501. Epub 2017 Nov 13.
Apolipoprotein (apo)A-I is an organizing scaffold protein that is critical to high-density lipoprotein (HDL) structure and metabolism, probably mediating many of its cardioprotective properties. However, HDL biogenesis is poorly understood, as lipid-free apoA-I has been notoriously resistant to high-resolution structural study. Published models from low-resolution techniques share certain features but vary considerably in shape and secondary structure. To tackle this central issue in lipoprotein biology, we assembled a team of structural biologists specializing in apolipoproteins and set out to build a consensus model of monomeric lipid-free human apoA-I. Combining novel and published cross-link constraints, small-angle X-ray scattering (SAXS), hydrogen-deuterium exchange (HDX) and crystallography data, we propose a time-averaged model consistent with much of the experimental data published over the last 40 years. The model provides a long-sought platform for understanding and testing details of HDL biogenesis, structure and function.
载脂蛋白（apo）A-I是一种组织支架蛋白，对高密度脂蛋白（HDL）的结构和代谢至关重要，可能介导了其许多心脏保护特性。然而，HDL的生物合成仍知之甚少，因为无脂apoA-I一直以来都极难进行高分辨率结构研究。低分辨率技术发表的模型具有某些共同特征，但在形状和二级结构上差异很大。为了解决脂蛋白生物学中的这一核心问题，我们组建了一个专门研究载脂蛋白的结构生物学家团队，并着手构建无脂人apoA-I单体的共识模型。结合新的和已发表的交联限制、小角X射线散射（SAXS）、氢-氘交换（HDX）和晶体学数据，我们提出了一个与过去40年发表的许多实验数据一致的时间平均模型。该模型为理解和测试HDL生物合成、结构和功能的细节提供了一个长期以来寻求的平台。
