Structural Basis for CD44 Recognition by ERM Proteins
Structural Basis for CD44 Recognition by ERM Proteins
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DOI：
10.1074/jbc.m803606200
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发表时间：
2008-10-24
影响因子：
4.8
通讯作者：
Hakoshima, Toshio
中科院分区：
文献类型：
--
作者：
Mori, Tomoyuki;Kitano, Ken;Hakoshima, Toshio
CD 44是一种重要的粘附分子，作为主要的透明质酸受体，在多种生理和病理过程中介导细胞粘附和迁移。尽管CD 44的完全活性需要结合到ERM（ezrin/radixin/moesin）蛋白，但由72个氨基酸残基组成的CD 44胞质区缺乏在细胞间粘附分子（ICAM）-2和免疫球蛋白超家族的其它粘附分子中发现的用于ERM结合的基序-1共有序列。超离心沉降研究和圆二色性测量揭示了一个扩展的单体形式的细胞质肽在溶液中。与CD 44胞质肽复合的根蛋白FERM结构域的晶体结构显示，肽的KKKLVIN序列形成β链，随后是结合FERM结构域的亚结构域C的短环结构。与基序1结合类似，CD 44 β链结合β 5C链和螺旋α 1C链之间的浅沟，并从亚结构域C增加β折叠β 5C-β 7 C。两个疏水性CD 44残基Leu和Ile对接到疏水性口袋中，在CD 44短环的Asn和亚结构域C的环β 4C-β 5C之间形成氢键。这种结合模式类似于NEP（中性内肽酶24.11）而不是ICAM-2。我们的结果揭示了ERM蛋白的FERM结构域对肽识别的特征性多功能性，提出了CD 44尾部通过调节膜内蛋白水解从细胞骨架释放以进行核转位的可能机制，并为Smad 1与结合ERM蛋白的活化CD 44的相互作用提供了结构基础。
CD44 is an important adhesion molecule that functions as the major hyaluronan receptor which mediates cell adhesion and migration in a variety of physiological and pathological processes. Although full activity of CD44 requires binding to ERM (ezrin/radixin/moesin) proteins, the CD44 cytoplasmic region, consisting of 72 amino acid residues, lacks the Motif-1 consensus sequence for ERM binding found in intercellular adhesion molecule (ICAM)-2 and other adhesion molecules of the immunoglobulin superfamily. Ultracentrifugation sedimentation studies and circular dichroism measurements revealed an extended monomeric form of the cytoplasmic peptide in solution. The crystal structure of the radixin FERM domain complexed with a CD44 cytoplasmic peptide reveals that the KKKLVIN sequence of the peptide forms a beta strand followed by a short loop structure that binds subdomain C of the FERM domain. Like Motif-1 binding, theCD44 beta strand binds the shallow groove between strand beta 5C and helix alpha 1C and augments the beta sheet beta 5C-beta 7C from subdomain C. Two hydrophobic CD44 residues, Leu and Ile, are docked into a hydrophobic pocket with the formation of hydrogen bonds between Asn of the CD44 short loop and loop beta 4C-beta 5C from subdomain C. This binding mode resembles that of NEP (neutral endopeptidase 24.11) rather than ICAM-2. Our results reveal a characteristic versatility of peptide recognition by the FERM domains from ERM proteins, suggest a possible mechanism by which the CD44 tail is released from the cytoskeleton for nuclear translocation by regulated intramembrane proteolysis, and provide a structural basis for Smad1 interactions with activated CD44 bound to ERM protein.