The CUL3 gene provides instructions for making a protein called cullin-3. This protein plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitin-proteasome system.
Cullin-3 is a core piece of a complex known as an E3 ubiquitin ligase. E3 ubiquitin ligases function as part of the ubiquitin-proteasome system by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to specialized cell structures known as proteasomes, which attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth.
E3 ubiquitin ligases containing the cullin-3 protein tag proteins called WNK1 and WNK4 with ubiquitin. These proteins are involved in controlling blood pressure in the body. By regulating the amount of WNK1 and WNK4 available, cullin-3 plays a role in blood pressure control.
At least 17 mutations in the CUL3 gene can cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). These mutations lead to production of an abnormally short cullin-3 protein that is missing a region. Studies show that this change alters the function of the E3 ubiquitin ligase complex. The change leads to impaired degradation of the WNK4 protein, although the exact mechanism is unclear. The resulting excess of WNK4 protein disrupts normal control of blood pressure, causing hypertension and other features of PHA2. It is unknown if WNK1 is affected by the alterations to the E3 ubiquitin ligase or whether WNK1 plays a role in PHA2 caused by CUL3 gene mutations.
- cullin-3 isoform 1
- cullin-3 isoform 2
- cullin-3 isoform 3