Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function
Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function
复制标题
DOI：
10.1073/pnas.0609174104
复制
发表时间：
2007-04-10
影响因子：
11.1
通讯作者：
Trowsdale, John
中科院分区：
文献类型：
--
作者：
James, Leo C.;Keeble, Anthony H.;Trowsdale, John
人类三重基序（TRIM）家族由70个成员组成，包括HIV限制因子TRIM 5 α和疾病相关蛋白TRIM 20（pyrin）和TRIM 21。TRIM蛋白具有保守的结构域结构，但具有不同的细胞作用。在这里，我们描述了C-末端PRYSPRY结构域如何介导不同的TRIM功能。TRIM 21 PRYSPRY与其靶IgG Fc复合的晶体结构揭示了由抗体样可变环形成的两个离散口袋组成的典型结合界面。该界面的丙氨酸扫描已经确定了控制TRIM 21与Fc结合的热点残基;相同的热点通过TRIM 5a控制HIV/鼠白血病病毒限制，并在TRIM 20/pyrin中介导严重的家族性地中海热。TRIM 21 PRYSPRY的IgG结合位点的表征揭示了TRIM 21作为类似于细菌蛋白A的超抗原，并表明抗体双极桥接机制可能有助于抗TRIM 21自身抗体免疫复合物在自身免疫性疾病中的致病性积累。
The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5 alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5a and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.