Cbl promotes clustering of endocytic adaptor proteins
Cbl promotes clustering of endocytic adaptor proteins
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DOI：
10.1038/nsmb1000
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发表时间：
2005-11-01
影响因子：
16.8
通讯作者：
Bravo, J
中科院分区：
文献类型：
--
作者：
Jozic, D;Cárdenes, N;Bravo, J
泛素连接酶c-Cbl和Cbl-b通过介导受体的多重单泛素化并促进其分选用于溶酶体降解而在受体下调中起关键作用。它们的功能通过与包括CIN 85和PIX的调节蛋白的相互作用来调节，所述调节蛋白识别Cbl中的脯氨酸-精氨酸基序，从而促进或抑制受体内吞作用。我们报告了CIN 85和β-PIX的SH 3结构域与来自Cbl-b的脯氨酸-精氨酸肽复合的结构。这两种结构都揭示了含有两个SH 3结构域的异源三聚体复合物，它们通过单个肽保持在一起。三聚化也发生在溶液中，并通过假对称肽序列促进。此外，CIN 85和Cbl的三元复合物在体内形成，并且对于Cbl促进表皮生长因子受体（EGFR）下调的能力是重要的。这些结果为Cbl控制受体下调的新机制提供了分子解释。
The ubiquitin ligases c-Cbl and Cbl-b play a crucial role in receptor downregulation by mediating multiple monoubiquitination of receptors and promoting their sorting for lysosomal degradation. Their function is modulated through interactions with regulatory proteins including CIN85 and PIX, which recognize a proline-arginine motif in Cbl and thus promote or inhibit receptor endocytosis. We report the structures of SH3 domains of CIN85 and beta-PIX in complex with a proline-arginine peptide from Cbl-b. Both structures reveal a heterotrimeric complex containing two SH3 domains held together by a single peptide. Trimerization also occurs in solution and is facilitated by the pseudo-symmetrical peptide sequence. Moreover, ternary complexes of CIN85 and Cbl are formed in vivo and are important for the ability of Cbl to promote epidermal growth factor receptor (EGFR) downregulation. These results provide molecular explanations for a novel mechanism by which Cbl controls receptor downregulation.