The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions
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Cai and Yang Cell Div (2016) 11:7 DOI 10.1186/s13008-016-0020-7
Open Access
REVIEW
The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions Weijia Cai* and Haifeng Yang*
Abstract Background: Cullin-RING E3 ubiquitin ligase complexes play a central role in targeting cellular proteins for ubiquitination-dependent protein turnover through 26S proteasome. Cullin-2 is a member of the Cullin family, and it serves as a scaffold protein for Elongin B and C, Rbx1 and various substrate recognition receptors to form E3 ubiquitin ligases. Main body of the abstract: First, the composition, structure and the regulation of Cullin-2 based E3 ubiquitin ligases were introduced. Then the targets, the biological functions of complexes that use VHL, Lrr-1, Fem1b, Prame, Zyg-11, BAF250, Rack1 as substrate targeting subunits were described, and their involvement in diseases was discussed. A small molecule inhibitor of Cullins as a potential anti-cancer drug was introduced. Furthermore, proteins with VHL box that might bind to Cullin-2 were described. Finally, how different viral proteins form E3 ubiquitin ligase complexes with Cullin-2 to counter host viral defense were explained. Conclusions: Cullin-2 based E3 ubiquitin ligases, using many different substrate recognition receptors, recognize a number of substrates and regulate their protein stability. These complexes play critical roles in biological processes and diseases such as cancer, germline differentiation and viral defense. Through the better understanding of their biology, we can devise and develop new therapeutic strategies to treat cancers, inherited diseases and viral infections. Keywords: Cullin-2, Elongin, E3 ubiquitin ligase, VHL, Hypoxia inducible factor, Rack1, E4orf6, Viral host defense Background Cullin-RING E3 ubiquitin ligase complexes (CRLs) play a central role in targeting cellular proteins for ubiquitination-dependent protein turnover through 26S proteasome [1]. Cullin-2 (Cul2), a member of Cullin family proteins, is encoded by CUL2. Cul2 functions as a scaffold protein to form CRLs that belong to the Elongin B and C-Cul2 or Cul5-SOCS box protein (ECS) family [2]. In CRL2 complexes, Cul2 assembles with RING protein (Rbx1) (also known as Roc1) as RING finger protein, Elongin B and C proteins as adapter proteins and various substrate recognition receptors [2, 3]. Cul2 is different from other most Cullins, which are evolutionarily conserved from yeast to human. Cul2 *Correspondence: [email protected]; [email protected] Department of Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
is present only in multi-cellular organisms and plays a particular function [4]. The most well-known CRL2 substrate recognition receptor is the tumor suppressor protein VHL that is mutated in von Hippel–Lindau (VHL) syndrome, a rare hereditary cancer syndrome [5]. Germline VHL mutations usually disrupt the interaction between VHL and Elongin B and C, and inactivate the VHL-Elongin B/C-
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