翻译2013-12翻译2013-12.docxVIP

Biochemistry.?2013 Dec 13. [Epub ahead of print]Molecular?Origin?of the?Binding?of?WWOX?Tumor?Suppressor?to?ErbB4?Receptor?Tyrosine?Kinase.Schuchardt BJ,?Bhat V,?Mikles DC,?McDonald CB,?Sudol M,?Farooq A.Author informationAbstractThe ability of?WWOX?tumor?suppressor?to physically associate with the intracellular domain (ICD) of?ErbB4?receptor?tyrosine?kinase?is believed to play a central role in downregulating the transcriptional function of the latter. Herein, using various biophysical methods, we show that while the WW1 domain of?WWOX?binds to PPXY motifs located within the ICD of?ErbB4?in a physiologically relevant manner, the WW2 domain does not. Importantly, while the WW1 domain absolutely requires the integrity of the PPXY consensus sequence, nonconsensus residues within and flanking this motif do not appear to be critical for?binding. This strongly suggests that the WW1 domain of?WWOX?is rather promiscuous toward its cellular partners. We also provide evidence that the lack of?binding?of the WW2 domain of?WWOX?to PPXY motifs is due to the replacement of a signature tryptophan, lining the hydrophobic ligand?binding?groove, with?tyrosine?(Y85). Consistent with this notion, the Y85W substitution within the WW2 domain exquisitely restores its?binding?to PPXY motifs in a manner akin to the?binding?of the WW1 domain of?WWOX. Of particular significance is the observation that the WW2 domain augments the?binding?of the WW1 domain to?ErbB4, implying that the former serves as a chaperone within the context of the WW1-WW2 tandem module of?WWOX?in agreement with our findings reported previously. Altogether, our study sheds new light on themolecular?basis of an important WW-ligand interaction involved in mediating a plethora of cellular processes.PMIDPubMed - as supplied by publisher]既往研究表明肿瘤抑制子WWOX通过与ErbB4的胞内结构域结合从而调控后者下游的转录功能。鉴于此，我们运用一系列生物物理学方法证实WWOX是通过其WW1结构域而不是WW2结构域与ErbB4胞内的PPXY结构域结合。我们发现WW1结构域仅和完整保守的PPXY模体结合，而在后者周围的不保守PPXY结构域与WW1没有结合。这些强烈表明WWOX的WW1结构在和胞内的P