Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
PLoS One. 2013 Apr 26;8(4):e62996. doi: 10.1371/journal.pone.0062996. Print 2013.
Hemoglobin (Hb) plays a critical role in human physiological function by transporting O2. Hb is safe and inert within the confinement of the red blood cell but becomes reactive and toxic upon hemolysis. Haptoglobin (Hp) is an acute-phase serum protein that scavenges Hb and the resulting Hb-Hp complex is subjected to CD163-mediated endocytosis by macrophages. The interaction between Hb and Hp is extraordinarily strong and largely irreversible. As the structural details of the human Hb-Hp complex are not yet available, this study reports for the first time on insights of the binding modalities and molecular details of the human Hb-Hp interaction by means of protein-protein docking. Furthermore, residues that are pertinent for complex formation were identified by computational alanine scanning mutagenesis. Results revealed that the surface of the binding interface of Hb-Hp is not flat and protrudes into each binding partner. It was also observed that the secondary structures at the Hb-Hp interface are oriented as coils and α-helices. When dissecting the interface in more detail, it is obvious that several tyrosine residues of Hb, particularly β145Tyr, α42Tyr and α140Tyr, are buried in the complex and protected from further oxidative reactions. Such finding opens up new avenues for the design of Hp mimics which may be used as alternative clinical Hb scavengers.
血红蛋白（Hb）通过运输 O2 在人体生理功能中起着至关重要的作用。在红细胞的限制内，Hb 是安全和惰性的，但在溶血时会变得反应性和毒性。触珠蛋白（Hp）是一种急性期血清蛋白，可清除 Hb，由此产生的 Hb-Hp 复合物被巨噬细胞通过 CD163 介导的内吞作用摄取。Hb 和 Hp 之间的相互作用非常强，而且在很大程度上是不可逆的。由于人类 Hb-Hp 复合物的结构细节尚不清楚，因此本研究首次通过蛋白质-蛋白质对接报告了人类 Hb-Hp 相互作用的结合方式和分子细节的见解。此外，通过计算丙氨酸扫描诱变鉴定了与复合物形成相关的残基。结果表明，Hb-Hp 结合界面的表面不平坦，并向每个结合伴侣突出。还观察到，Hb-Hp 界面的二级结构呈卷曲和α-螺旋。当更详细地剖析界面时，显然 Hb 的几个酪氨酸残基，特别是β145Tyr、α42Tyr 和 α140Tyr，被埋藏在复合物中，并免受进一步的氧化反应。这一发现为 Hp 模拟物的设计开辟了新的途径，Hp 模拟物可用作替代临床 Hb 清除剂。
