西亚试剂：Targeting WW domains linker of HECT-type ubiquitin ligase S

Targeting WW domains linker of HECT-type ubiquitin ligase Smurf1 for activation by CKIP-1
Kefeng Lu1,4, Xiushan Yin1,4, Tujun Weng2, Shenli Xi1, Li Li1, Guichun Xing1, Xuan Cheng2, Xiao Yang2, Lingqiang Zhang1 & Fuchu He1,3

E3 ubiquitin ligases are final effectors of the enzyme cascade controlling ubiquitylation1. A central issue in understanding their regulation is to decipher mechanisms of their assembly and activity2. In contrast with RING-type E3s, fewer mechanisms are known for regulation of HECT-type E3s2, 3, 4. Smad ubiquitylation regulatory factor 1 (Smurf1), a C2-WW-HECT-domain E3, is crucial for bone homeostasis, in which it suppresses osteoblast activity5, 6. However, whether and how its activity is regulated remains unclear. Here we show that Smurf1, but not Smurf2, interacts with casein kinase-2 interacting protein-1 (CKIP-1), resulting in an increase in its E3 ligase activity. Surprisingly, CKIP-1 targets specifically the linker region between the WW domains of Smurf1, thereby augmenting its affinity for and promoting ubiquitylation of the substrate. Moreover, CKIP-1-deficient mice undergo an age-dependent increase in bone mass as a result of accelerated osteogenesis and decreased Smurf1 activity. These findings provide evidence that the WW domains linker is important in complex assembly and in regulating activity of HECT-type E3s and that CKIP-1 functions as the first auxiliary factor to enhance the activation of Smurf1.

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