Selective compounds enhance osteoblastic activity by targeting HECT domain of ubiquitin ligase Smurf1
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Yuan Zhang1, Cheng Wang1,2, Yu Cao1,3, Yongqing Gu1,2 and Lingqiang Zhang1
1State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
2Department of Basic Medical Sciences, School of Medicine, Shihezi University, Shihezi, Xinjiang Province 832000, China
3Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Lingqiang Zhang, email: email@example.com
Keywords: Smurf1, HECT domain, Ub binding region, ubiquitination, osteoblastic activity
Received: March 30, 2016 Accepted: May 29, 2016 Published: July 18, 2016
The HECT-type ubiquitin ligase Smurf1 (Smad ubiquitination regulatory factor-1) plays the prominent role in regulation of bone formation, embryonic development, and tumorigenesis by directing the ubiquitin-proteasomal degradation of specific targets. In contrast with RING-type E3s, the catalytic HECT domain of Smurf1 firstly binds to and then transfers ubiquitin (Ub) molecules onto the substrates. The Smurf1-Ub interaction is required for Smurf1 catalytic ligase activity to promote substrate degradation. However, so far specific regulators or compounds controlling Smurf1-Ub interaction and the ligase activity have not been identified. Here we report two small molecule compounds targeting Ub binding region of HECT domain interrupt Smurf1-Ub contact, inhibit Smurf1 ligase activity and stabilize BMP signal components Smad1/5 protein level. Furthermore, these compounds increase BMP signal responsiveness and enhance osteoblastic activity in cultured cells. These findings provide a novel strategy through targeting Smurf1 ligase activity to potentially treat bone disorders such as osteoporosis.
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