- Cullin-2 (CUL2) is a member of the cullin family of scaffold proteins that form the structural backbone of Cullin–RING ubiquitin ligases (CRLs), a large class of E3 ligase complexes that mediate the ubiquitination and proteasomal degradation of key regulatory proteins.
- The cullin family is defined by their ability to act as molecular scaffolds, bringing together substrate-recognition modules with ubiquitin-conjugating enzymes. Cullin-2 is encoded by the CUL2 gene and is most widely recognized for its role in assembling the von Hippel–Lindau (VHL) E3 ubiquitin ligase complex, a critical regulator of the hypoxia-inducible factor (HIF) pathway. Through this function, Cullin-2 is central to oxygen sensing, angiogenesis, and tumor suppression.
- Structurally, Cullin-2 serves as a rigid molecular platform that coordinates two distinct modules of the E3 ligase machinery. Its N-terminal domain binds adaptor proteins—typically the elongin B/C heterodimer—that connect Cullin-2 to the VHL protein or other substrate recognition proteins. Its C-terminal domain associates with Rbx1 (also known as ROC1), a RING finger protein that recruits E2 ubiquitin-conjugating enzymes charged with ubiquitin. In this way, Cullin-2 positions the substrate and the ubiquitin-transfer machinery in close proximity, catalyzing the efficient ubiquitination of target proteins.
- The best-characterized role of Cullin-2 is in the VHL–elongin B/C–Cullin-2–Rbx1 (VCB-CUL2-Rbx1) complex, which regulates the stability of HIF-α subunits. Under normoxic conditions, HIF-α is hydroxylated on specific proline residues by prolyl hydroxylase domain proteins (PHDs). This modification allows the VHL protein to recognize and bind HIF-α, bringing it into the Cullin-2 complex. Once bound, Cullin-2 positions HIF-α for polyubiquitination by Rbx1-bound E2 enzymes, leading to its rapid proteasomal degradation. Under hypoxic conditions, hydroxylation does not occur, HIF-α escapes degradation, and it accumulates to drive hypoxia-responsive gene expression. Thus, Cullin-2 is essential in oxygen homeostasis by acting as a scaffold for HIF regulation.
- Beyond the VHL pathway, Cullin-2 participates in additional E3 ubiquitin ligase assemblies with other substrate-recognition proteins, extending its regulatory roles to processes such as cell cycle progression, signal transduction, and protein quality control. For example, Cullin-2 has been linked to complexes that regulate proteins involved in cytoskeletal dynamics and cell division. This versatility underscores its broader role as a scaffold protein that can be repurposed by different adaptors to target diverse substrates for ubiquitination.
- In disease, Cullin-2 has strong clinical relevance because of its central involvement in the VHL tumor suppressor pathway. Mutations in VHL, rather than Cullin-2 itself, are most frequently responsible for pathologies such as clear cell renal cell carcinoma and VHL disease, a hereditary cancer syndrome characterized by hemangioblastomas, renal tumors, and pheochromocytomas. However, Cullin-2’s essential role in assembling the functional VHL complex means its dysfunction or misregulation could also compromise HIF-α degradation and contribute to tumorigenesis. Emerging studies suggest that Cullin-2 may also play roles in viral pathogenesis, as some viruses hijack cullin-based ligases to degrade host restriction factors, further highlighting its biological importance.
