Abrahamson S L, Wu H M, Williams R E, Der K, Ottah N, Little R, Gazzano-Santoro H, Theofan G, Bauer R, Leigh S, Orme A, Horwitz A H, Carroll S F, Dedrick R L
XOMA Corporation, Berkeley, California 94710 and the XOMA Corporation, Santa Monica, California 90404, USA.
J Biol Chem. 1997 Jan 24;272(4):2149-55. doi: 10.1074/jbc.272.4.2149.
The physiological response to endotoxin (lipopolysaccharide (LPS)) can be regulated by two closely related LPS-binding proteins, LPS-binding protein (LBP), which potentiates LPS' inflammatory activity via interaction with the monocytic antigen CD14, and bactericidal/permeability-increasing protein (BPI), which neutralizes LPS. Both proteins bind LPS with high affinity sites in their N-terminal domains, whereas interaction between LBP and CD14 is dependent upon the LBP C-terminal domain. We have created fusions of the N- and C-terminal domains from each protein and compared the functional activities and pharmacokinetics of these fusions, the individual N-terminal domains, and the parent proteins. The N-terminal domains of BPI and LBP bound lipid A with their characteristic apparent affinity constants, regardless of the C-terminal fusion partner. In addition, the C-terminal domain of LBP allowed transfer of LPS to CD14 in conjunction with either N-terminal LPS binding domain. Proteins containing a BPI N-terminal domain had greater heparin binding capacities in vitro and were cleared more rapidly from the plasma of whole animals. Taken together, these data better define how closely related proteins such as BPI and LBP can have opposing effects on the body's response to LPS.
对内毒素（脂多糖，LPS）的生理反应可由两种密切相关的LPS结合蛋白调节，即LPS结合蛋白（LBP），它通过与单核细胞抗原CD14相互作用增强LPS的炎症活性；以及杀菌/通透性增加蛋白（BPI），它可中和LPS。这两种蛋白均在其N端结构域通过高亲和力位点结合LPS，而LBP与CD14之间的相互作用则依赖于LBP的C端结构域。我们构建了每种蛋白N端和C端结构域的融合体，并比较了这些融合体、单个N端结构域及亲本蛋白的功能活性和药代动力学。无论C端融合伴侣如何，BPI和LBP的N端结构域均以其特征性的表观亲和常数结合脂多糖。此外，LBP的C端结构域可与任一N端LPS结合结构域协同将LPS转移至CD14。含有BPI N端结构域的蛋白在体外具有更高的肝素结合能力，并且在全动物血浆中清除更快。综上所述，这些数据更清楚地阐明了BPI和LBP等密切相关的蛋白如何对机体对LPS的反应产生相反的作用。
