Rossjohn J, Cappai R, Feil S C, Henry A, McKinstry W J, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters C L, Parker M W
The Ian Potter Foundation Protein Crystallography Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Nat Struct Biol. 1999 Apr;6(4):327-31. doi: 10.1038/7562.
Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of an effective therapy. Here we describe the 1.8 A resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28-123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth factors, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo.
淀粉样前体蛋白（APP）在阿尔茨海默病中起着核心作用。APP的一种蛋白水解分解产物，称为β-淀粉样蛋白，是在阿尔茨海默病患者大脑中发现的弥漫性和纤维状沉积物的主要成分。尽管进行了大量研究，但APP的正常生理功能在很大程度上仍不清楚。了解其功能不仅有助于深入了解该疾病的发病机制，而且在开发有效治疗方法方面可能也至关重要。在此，我们描述了APP N端肝素结合结构域（第28 - 123位氨基酸残基）的1.8埃分辨率晶体结构，该结构除其他功能外，还负责刺激神经突生长。该结构揭示了一个可能与大脑中的糖胺聚糖相互作用的高度带电的碱性表面，以及一个与之相邻的疏水表面，据推测该疏水表面在诸如二聚化或配体结合等重要功能中发挥作用。与富含半胱氨酸的生长因子的结构相似性，再加上其已知的促进生长特性，表明APP N端结构域在体内可能具有生长因子的功能。
