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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity
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Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity

机译：串联Smad泛素化调节因子（Smurf）WW域的耦合调节靶标特异性

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摘要

Smad ubiquitination regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that participates in degradation of TGF-β receptors and other targets. Smurf2 WW domains recognize PPXY (PY) motifs on ubiquitin ligase target proteins or on adapters, such as Smad7, that bind to E3 target proteins. We previously demonstrated that the isolated WW3 domain of Smurf2, but not the WW2 domain, can directly bind to a Smad7 PY motif. We show here that the WW2 augments this interaction by binding to the WW3 and making auxiliary contacts with the PY motif and a novel E/D-S/T-P motif, which is N-terminal to all Smad PY motifs. The WW2 likely enhances the selectivity of Smurf2 for the Smad proteins. NMR titrations confirm that Smad1 and Smad2 are bound by Smurf2 with the same coupled WW domain arrangement used to bind Smad7. The analogous WW domains in the short isoform of Smurf 1 recognize the Smad7 PY peptide using the same coupled mechanism. However, a longer Smurf1 isoform, which has an additional 26 residues in the inter-WW domain linker, is only partially able to use the coupled WW domain binding mechanism. The longer linker results in a decrease in affinity for the Smad7 peptide. Interdomain coupling of WW domains enhances selectivity and enables the tuning of interactions by isoform switching.
机译：Smad泛素化调节因子2（Smurf2）是一种E3泛素连接酶，参与TGF-β受体和其他靶标的降解。 Smurf2 WW域识别泛素连接酶靶蛋白或与E3靶蛋白结合的衔接子（例如Smad7）上的PPXY（PY）基序。先前我们证明了Smurf2的分离的WW3域，而不是WW2域，可以直接与Smad7 PY基序结合。我们在这里显示，WW2通过绑定到WW3并与PY图案和一个新颖的E / D-S / T-P图案（与所有Smad PY图案的N端是N端）进行辅助接触而增强了这种相互作用。 WW2可能会增强Smurf2对Smad蛋白的选择性。 NMR滴定证实Smad1和Smad2被Smurf2结合，并具有与结合Smad7相同的偶联WW域排列。 Smurf 1的短同工型中的类似WW域使用相同的偶联机制识别Smad7 PY肽。但是，更长的Smurf1亚型在WW域间接头中具有26个残基，只能部分使用耦合的WW域结合机制。较长的接头导致对Smad7肽的亲和力降低。 WW域的域间耦合增强了选择性，并能够通过亚型转换来调节相互作用。

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    P. Andrew Chong; Hong Lin; Jeffrey L. Wrana; Julie D. Forman-Kay;

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    Program in Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8;

    rnProgram in Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8;

    rnDepartment of Medical Genetics and Microbiology, University of Toronto, Toronto, ON, Canada M5S 1A8 Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5;

    rnProgram in Molecular Structure and Function, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 Department of Biochemistry, University of Toronto, Toronto, ON, Canada M5S 1A8;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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