Letter abstract
Nature Cell Biology 10, 994 - 1002 (2008)
Published online: 20 July 2008 | doi:10.1038/ncb1760
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.
- State Key Laboratory of Proteomics, Beijing Proteomics Research Center, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, China.
- Genetic Laboratory of Development and Diseases, Beijing Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
- These authors contributed equally to this work.
Correspondence to: Fuchu He1,3 hefc@nic.bmi.ac.cn
Correspondence to: Lingqiang Zhang1 zhanglq@nic.bmi.ac.cn
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Human therapeutic proteins from silkwormsNature Biotechnology Research News (01 Jan 2003)
RESEARCH
A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteinsNature Immunology Article (01 Jun 2001)
TIRAP: an adapter molecule in the Toll signaling pathwayNature Immunology Article (01 Sep 2001)
See all 14 matches for Research
