Major Vault Protein: Function, Structure, and Cancer Role
Examine the major vault protein, a cellular component with key biological roles that is also a significant factor in how cancer cells resist treatment.
Within the cytoplasm of most complex cells are microscopic structures known as vault particles. These ribonucleoprotein complexes were first identified in 1986 and named for their resemblance to the vaulted ceilings of cathedrals. The primary building block of these cellular components is the Major Vault Protein (MVP), which accounts for the vast majority of the particle’s total mass. MVP is a protein encoded by the MVP gene, and the repetitive assembly of this single protein gives the vault particle its signature architecture.
The Structure of Cellular Vaults
The architecture of a vault particle is a distinct, hollow, barrel-shaped container. This structure is large by cellular standards, measuring approximately 41 by 72.5 nanometers, which is several times the size of a ribosome. In mammals, each vault is constructed from 78 individual MVP units that interlock to form two identical, cup-shaped halves. These two halves come together to create the complete, enclosed barrel.
This protein shell accounts for over 70% of the vault’s mass. The hollow interior contains several other molecules, including two other proteins: TEP1, which is also associated with telomerase, and VPARP, a type of polymerase. Additionally, each vault particle encapsulates a small, untranslated RNA molecule known as vault RNA (vRNA). These components reside within the protected lumen of the MVP-based structure.
Biological Roles of Major Vault Protein
One of the most supported roles for the Major Vault Protein is in cellular transport. The barrel-like structure is thought to act as a transport container, shuttling molecules like proteins and messenger RNA (mRNA) between the cell’s nucleus and the cytoplasm. This movement is facilitated by the vault’s ability to associate with the nuclear pore complex, the gateway to the nucleus.
Beyond transport, MVP is involved in regulating cell signaling pathways. It interacts with proteins in pathways such as the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) cascades, which govern cell growth and survival. By binding to signaling proteins, MVP can modulate their activity, helping to fine-tune the cell’s response to external stimuli.
MVP also contributes to the innate immune system. The protein is involved in the cellular response to viral infections and other pathogens. For instance, it can influence the signaling pathways activated by interferons, which are molecules that signal the presence of an invader. This suggests that vault particles are part of the cell’s first line of defense.
Connection to Multidrug Resistance in Cancer
A significant area of study for Major Vault Protein is its connection to multidrug resistance (MDR) in cancer cells. MDR is a phenomenon where cancer cells become insensitive to a broad range of chemotherapy drugs, making treatment difficult. Many drug-resistant cancer cell lines have significantly elevated levels of MVP. This overexpression is a potential marker for predicting a poor response to chemotherapy in cancers like ovarian and lung cancer.
The leading hypothesis for how MVP contributes to MDR centers on the transport function of the vault particle. In cancer cells that overproduce MVP, the abundant vault particles are thought to capture chemotherapy agents that have entered the cell. Once encapsulated, the drugs are sequestered from their cellular targets, such as the DNA in the nucleus. The vaults may then transport these drugs out of the cell, rendering the treatment ineffective.
This protective mechanism turns a normal cellular process into a defense system for the tumor. The same transport capability that serves healthy cells is co-opted by cancer cells to eject the substances designed to destroy them. This link between high MVP expression and treatment failure makes the protein a subject of intense focus in oncology research.
Current Research and Therapeutic Potential
Given the role of Major Vault Protein in drug resistance, research is focused on counteracting its effects in cancer treatment. One strategy involves developing inhibitor molecules that can block the function of vault particles, restoring the sensitivity of cancer cells to treatment. Another approach uses genetic tools like small interfering RNA (siRNA) to specifically target and reduce the expression of the MVP gene, lowering the number of vault particles.
Scientists are also exploring how to use the vault particle’s unique structure for therapeutic benefit. Because vaults are naturally occurring in human cells, they are biocompatible and do not typically trigger an immune response. Researchers are bioengineering empty vault particles to serve as “nanocapsules” for targeted drug delivery. Therapeutic agents can be loaded into the hollow interior of these engineered vaults.
These drug-filled nanocapsules can be modified on their exterior to recognize and bind to specific receptors found only on cancer cells. This allows for the precise delivery of chemotherapy directly to the tumor, sparing healthy tissues and reducing side effects. This innovative use of vaults transforms a protein associated with drug resistance into a vehicle for more effective therapies.