Variable dimerization of the Ly49A natural killer cell receptor results in differential engagement of its MHC class I ligand
Variable dimerization of the Ly49A natural killer cell receptor results in differential engagement of its MHC class I ligand
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DOI：
10.1016/j.jmb.2006.07.005
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发表时间：
2006-09-08
影响因子：
5.6
通讯作者：
Mariuzza, Roy A.
中科院分区：
文献类型：
--
作者：
Dam, Julie;Baber, James;Mariuzza, Roy A.
自然杀伤(NK)细胞在检测和清除病毒感染和肿瘤细胞方面发挥着至关重要的作用。NK受体Ly49家族通过感知靶细胞上的主要组织相容性复合体(MHC)1类分子来调节NK细胞的功能。以前的晶体研究表明，Ly49A同源二聚体以不对称的方式结合一个MHC分子，而Ly49C同源二聚体以对称的方式结合两个MHC。此外，结合的受体具有明显不同的同源二聚体形式：Ly49A为“闭合状态”，Ly49C为“开放状态”。MHC分子之间的空间碰撞会阻止闭合的Ly49A二聚体以开放的Ly49C二聚体的方式与两个MHC结合。为了确定单个Ly49受体是否经历构象转换，使它们以不同的方式结合MHC，我们在偶极耦合技术的辅助下对未结合的Ly49A进行了溶液核磁共振研究。这项研究表明，在溶液中，未连接的Ly49A采用了与先前看到的Ly49C类似的对称、开放状态的同源二聚体构象。因此，Ly49A既可以处于关闭状态，也可以处于打开状态。为了研究Ly49A二聚体是否能与溶液中的两个MHC分子结合，除了观察到晶体中的一个MHC分子结合外，我们还进行了分析超速离心实验。速度沉淀法表明Ly49A二聚体可以与溶液中的两个MHC分子结合，这与核磁共振结果一致，表明未结合的Ly49A主要存在于开放状态。爱思唯尔有限公司出版。
Natural killer (NK) cells play a vital role in the detection and elimination of virally infected and tumor cells. The Ly49 family of NK receptors regulates NK cell function by sensing major histocompatibility complex (MHC) class 1 molecules on target cells. Previous crystal studies revealed that the Ly49A homodimer binds one MHC molecule in an asymmetric interaction, whereas the Ly49C homodimer binds two MHC in a symmetrical fashion. Moreover, the bound receptors adopt distinctly different homodimeric forms: a "closed state" for Ly49A and an "open state" for Ly49C. Steric clashes between MHC molecules would preclude the closed Ly49A dimer from engaging two MHC in the manner of the open Ly49C dimer. To determine whether individual Ly49 receptors can undergo a conformational switch enabling them to bind MHC in different ways, we carried out a solution NMR study of unbound Ly49A, aided by dipolar coupling technology. This study reveals that, in solution, unligated Ly49A adopts a symmetric, open-state, homodimer conformation similar to that seen previously for Ly49C. Hence, Ly49A can assume both closed and open states. To address whether the Ly49A dimer can bind two MHC molecules in solution, besides the binding of one MHC observed in the crystal, we carried out analytical ultracentrifugation experiments. Velocity sedimentation demonstrates that the Ly49A dimer can engage two MHC molecules in solution, in agreement with NMR results showing that unbound Ly49A exists predominantly in the open state. Published by Elsevier Ltd.