Fedorov A A, Ball T, Mahoney N M, Valenta R, Almo S C
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Structure. 1997 Jan 15;5(1):33-45. doi: 10.1016/s0969-2126(97)00164-0.
The profilins are a group of ubiquitous actin monomer binding proteins that are responsible for regulating the normal distribution of filamentous actin networks in eukaryotic cells. Profilins also bind polyphosphoinositides, which can disrupt the profilin-action complex, and proline-rich ligands which localize profilin to sites requiring extensive actin filament accumulation. Profilins represent cross-reactive allergens for almost 20 % of all pollen allergic patients.
We report the X-ray crystal structure of birch pollen profilin (BPP) at 2.4 resolution. The major IgE-reactive epitopes have been mapped and were found to cluster on the N- and C-terminal alpha helices and a segment of the protein containing two strands of the beta sheet. The overall fold of this protein is similar to that of the mammalian and amoeba profilins, however, there is a significant change in the orientation of the N-terminal alpha helix in BPP. This change in orientation alters the topography of a hydrophobic patch on the surface of the molecule, which is thought to be involved in the binding of proline-rich ligands.
Profilin has been identified as an important cross-reactive allergen for patients suffering from multivalent type I allergy. The prevalent epitopic areas are located in regions with conserved sequence and secondary structure and overlap the binding sites for natural profilin ligands, indicating that the native ligand-free profilin acts as the original cross-sensitizing agent. Structural homology indicates that the basic features of the G actin-profilin interaction are conserved in all eukaryotic organisms, but suggests that mechanistic differences in the binding of proline-rich ligands may exist. The structure of BPP provides a molecular basis for understanding allergen cross-reactivity.
肌动蛋白结合蛋白是一类广泛存在的肌动蛋白单体结合蛋白，负责调节真核细胞中丝状肌动蛋白网络的正常分布。肌动蛋白结合蛋白还能结合多磷酸肌醇，这会破坏肌动蛋白结合蛋白作用复合物，以及富含脯氨酸的配体，后者将肌动蛋白结合蛋白定位到需要大量肌动蛋白丝积累的位点。对于近20%的花粉过敏患者来说，肌动蛋白结合蛋白是交叉反应性过敏原。
我们报道了桦树花粉肌动蛋白结合蛋白（BPP）在2.4埃分辨率下的X射线晶体结构。已绘制出主要的IgE反应性表位，发现它们聚集在N端和C端α螺旋以及包含β折叠两条链的一段蛋白质上。该蛋白质的整体折叠与哺乳动物和变形虫的肌动蛋白结合蛋白相似，然而，BPP中N端α螺旋的方向有显著变化。这种方向变化改变了分子表面疏水斑块的拓扑结构，该疏水斑块被认为参与富含脯氨酸配体的结合。
肌动蛋白结合蛋白已被确定为患有多价I型过敏患者的重要交叉反应性过敏原。普遍的表位区域位于具有保守序列和二级结构的区域，并且与天然肌动蛋白结合蛋白配体的结合位点重叠，这表明天然无配体的肌动蛋白结合蛋白作为最初的交叉致敏剂。结构同源性表明，G肌动蛋白-肌动蛋白结合蛋白相互作用的基本特征在所有真核生物中都是保守的，但表明在富含脯氨酸配体结合方面可能存在机制差异。BPP的结构为理解过敏原交叉反应性提供了分子基础。
