Formation of assemblies on cell membranes by secreted proteins: molecular studies of free λ light chain aggregates found on the surface of myeloma cells
Formation of assemblies on cell membranes by secreted proteins: molecular studies of free λ light chain aggregates found on the surface of myeloma cells
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DOI：
10.1042/bj20130575
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发表时间：
2013-09-15
影响因子：
4.1
通讯作者：
Ramsland, Paul A.
中科院分区：
文献类型：
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作者：
Hutchinson, Andrew T.;Malik, Ansha;Ramsland, Paul A.
我们已经描述了骨髓瘤细胞表面存在与细胞膜相关的kappa flc(游离免疫球蛋白轻链)。值得注意的是，抗Kappa FLC单抗(单抗)MDX-1097正在临床试验中作为治疗Kappa轻链同型多发性骨髓瘤的方法进行评估。尽管抗FLC单抗具有临床应用潜力，但在分子水平上对膜相关FLC的研究有限。此外，目前尚不清楚lambda Flc是否能与骨髓瘤细胞的细胞膜结合。在本文中，我们描述了在骨髓瘤细胞表面存在的lambda Flc。我们发现，细胞表面相关的lambda flc直接结合到膜上，并以聚集的形式存在。随后，膜相互作用研究表明，lambda flc与饱和的两性离子脂类如磷脂酰胆碱和磷脂酰乙醇胺相互作用，并通过自动对接，我们表征了这些脂类的潜在识别位点。原子力显微镜证实膜相关的lambda flc是聚集的。考虑到目前的发现，我们提出了一个模型，即单个Flc对两性离子脂类显示出适度的亲和力，由于多价性，聚集稳定了相互作用。值得注意的是，这是第一次对结合到磷脂上的Flc进行成像，并为这种独特的骨髓瘤表面抗原与膜结合的可能机制提供了重要的见解。
We have described the presence of cell-membrane-associated kappa FLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-kappa FLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for kappa light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether lambda FLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of lambda FLCs on the surface of myeloma cells. We found that cell-surface-associated lambda FLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that lambda FLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated lambda FLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen.