WELLCOME TO LONDON BIOTECH Website-Recombinant Proteins, Antibodies, High-throughput Screening, R&D development
Journal of Bioequivalence & Bioavailability5 (2013): 248-252. doi: 10.4172/jbb.10000168.
The next step for the company is to carry out clinical trial to see the novel drug can be used in human cardiovascular diseases, including toxicity test as higher dose of drug may has toxicity effect. For more details and licensing and collaboration opportunities , Contact Dr. Weiming Xu
New Pathway on Cholesterol Regulation has been found. The breakthrough has come from our research work using proteomic and protein-protein interaction experiments. An E3 ligase, c-IAP1 has been found to process and ubiquitinate PCSK9 with K27 polyubiquitination, which target the PCSK9/LDLR to lysosome. The novel pathway descibed in the paper will open new avenues for cardivascular disease as PCSK9 now being considered as the hottest genetic validated target after statin.
Xu, W.; Liu, L.; Hornby, D. c-IAP1 Binds and Processes PCSK9 Protein: Linking the c-IAP1 in a TNF-α Pathway to PCSK9-Mediated LDLR Degradation Pathway. Molecules 2012, 17, 12086-12101.
Abstract: Recent genetic studies have shown that PCSK9, one of the key genes in cholesterol metabolism, plays a critical role by controlling the level of low-density lipoprotein receptor. However, how PCSK9 mediates LDLR degradation is still unknown. By combining a shotgun proteomic method and differential analysis of natural occurring mutations of the PCSK9 gene, we found that an E3 ubiquitin ligase c-IAP1 binds and processes PCSK9 protein. One of the ‘gain-of-function’ mutations, S127R, is defective with respect to binding to c-IAP1, and thus has defective autocatalytic activity. Knockdown of c-IAP1 impairs PCSK9 processing and autocatalytic cleavage. In c-IAP1 null mouse embryonic fibroblasts (MEFs), there is a dramatic decrease in secreted mature PCSK9 protein accompanied by a significant increase in LDLR protein levels compared with matched wild-type MEF cells. c-IAP1 also acts as an E3 ligase for ubiquitination of PCSK9. Ubiquitin containing only lysine-27 mediated PCSK9 ubiquitination by c-IAP1. Given K27-linked polyubiquitination promotes lysosomal localization, the finding indicates the c-IAP1 acts on both secretion of PCSK9 and its lysosomal localization. The novel pathway described here will open new avenues for exploring novel disease treatments.
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