MELTF - melanotransferrin |Elisa - Clia - Antibody - Protein

Background

Melanotransferrin (MELTF) is a cell-surface glycoprotein belonging to the transferrin family of iron-binding proteins, which also includes serum transferrin and lactoferrin. Unlike these other transferrins, which circulate in blood plasma or bodily secretions to transport iron, MELTF is primarily membrane-bound. Initially identified in melanoma cells, MELTF is now known to be widely expressed on the cell surface of a variety of tissues and has been implicated in cellular iron metabolism and immune functions. This protein is of particular interest in oncology and neurodegenerative research, as its overexpression has been observed in certain cancers and neurodegenerative diseases.

The primary role of MELTF is thought to involve iron binding and cellular iron transport, but its full range of functions is not completely understood. Due to its structure and iron-binding capabilities, MELTF is believed to play roles in oxidative stress response and iron homeostasis, both crucial for maintaining cellular function and mitigating the damage caused by reactive oxygen species (ROS). The protein is also being studied for its potential role in cancer cell proliferation, migration, and angiogenesis.

Protein Structure

MELTF shares structural similarities with other transferrin family members but has unique features that allow it to be membrane-bound. Structurally, MELTF can be divided into three main domains:

N-lobe and C-lobe Domains:

• Like other transferrins, MELTF has two lobes, the N-lobe and C-lobe, which together form a bilobal structure. Each lobe can bind a single ferric ion (Fe³⁺) in association with a bicarbonate anion. This structure is crucial for MELTF's role in iron binding and potential transport functions.
• The N-lobe and C-lobe each contain specific iron-binding sites. Unlike serum transferrin, which releases iron under acidic conditions (such as in endosomes), MELTF binds iron more tightly and does not easily release it, even at lower pH levels. This suggests a unique mechanism for iron utilization that might be relevant in specific tissues or disease contexts.

Glycosylation Sites:

• MELTF has several N-linked glycosylation sites that are important for its stability, localization, and interaction with other proteins. Glycosylation helps in stabilizing the protein structure and possibly influences its interactions with ligands and cell surface receptors.
• The glycosylation also appears to be essential in maintaining the protein’s orientation and activity on the cell surface, as glycosylated regions may help MELTF evade immune surveillance in cancer cells.

GPI Anchor:

• MELTF is uniquely characterized by a glycosylphosphatidylinositol (GPI) anchor at its C-terminus, which attaches it to the cell membrane. This is a key structural difference from serum transferrin and gives MELTF its membrane-bound property.
• The GPI anchor allows MELTF to localize specifically to lipid rafts—specialized microdomains within the cell membrane—where it may participate in signaling pathways related to iron uptake or other functions.

Classification and Subtypes

MELTF belongs to the transferrin family and is classified as a membrane-associated transferrin due to its GPI anchor. Unlike other transferrins, which circulate freely in plasma, MELTF is bound to cell membranes and thus operates in a different cellular context.

There are no widely recognized subtypes of MELTF, but the protein may undergo various post-translational modifications (e.g., glycosylation changes) depending on tissue type and disease state. These modifications could affect its functional properties, particularly in cancer cells where glycosylation patterns are often altered.

Function and Biological Significance

The functions of MELTF are still being explored, but current research highlights several key roles:

Iron Homeostasis:

• MELTF’s primary function appears to be related to iron binding and, possibly, transport. Although it binds iron similarly to serum transferrin, it does not release iron readily, suggesting it may store or buffer iron rather than transport it across membranes. This property may be beneficial in tissues where iron needs to be tightly regulated to prevent oxidative damage.
• MELTF may also play a role in protecting cells from iron-mediated toxicity by binding excess iron ions, which could otherwise catalyze the formation of ROS.

Cell Proliferation and Migration:

• In cancer cells, MELTF is overexpressed, which suggests it could play a role in cellular proliferation, migration, and tumor growth. The exact mechanism is unclear, but it is hypothesized that MELTF’s role in iron handling and cell surface interactions may be involved in enhancing cancer cell metabolism and invasive capacity.
• Additionally, MELTF may be involved in angiogenesis, or blood vessel formation, an essential process for tumor growth and metastasis, as it supplies the cancer cells with nutrients and oxygen.

Immune Function and Neuroprotection:

• MELTF may interact with immune cells and play a role in modulating the immune response, although this function is less well-understood. Given its expression in specific tissues, it may help modulate local iron availability during inflammatory responses.
• MELTF has also been studied in the context of neurodegenerative diseases. Elevated MELTF levels have been observed in the brains of patients with Alzheimer’s disease and other neurodegenerative disorders, suggesting it may be involved in protecting neurons from iron-related oxidative stress, or alternatively, that it could contribute to neurodegeneration under certain pathological conditions.

Clinical Issues

MELTF’s dysregulation and overexpression have been implicated in various pathological conditions:

Cancer:

• MELTF is overexpressed in several cancers, including melanoma, breast cancer, and pancreatic cancer. Its overexpression may enhance cancer cell survival, proliferation, and metastasis. In these contexts, MELTF could contribute to iron sequestration and storage, supporting the high metabolic demands of tumor cells.
• MELTF’s overexpression in cancer has made it a potential biomarker for cancer diagnosis and prognosis. Efforts are underway to explore MELTF-targeted therapies, particularly for cancers where MELTF plays a prominent role in tumor progression.

Neurodegenerative Diseases:

• Elevated levels of MELTF have been noted in neurodegenerative diseases, including Alzheimer’s disease. The exact role of MELTF in these conditions is not fully understood, but it may be involved in abnormal iron accumulation, which is a common feature in neurodegenerative pathology. High MELTF levels in neural tissues might contribute to iron imbalance and exacerbate oxidative stress in neurons.
• Further research is necessary to determine whether MELTF could be a therapeutic target for managing iron levels in the brain and protecting against neurodegeneration.

Iron Metabolism Disorders:

• Given its role in iron handling, MELTF may also be relevant in disorders of iron metabolism. However, due to its membrane-bound nature, its exact contribution to systemic iron homeostasis is still under investigation. Abnormalities in MELTF expression or function could potentially contribute to conditions involving iron overload or deficiency.

Summary

MELTF (melanotransferrin) is a GPI-anchored, membrane-bound glycoprotein in the transferrin family. It has a bilobal structure with iron-binding sites, similar to other transferrins, but does not readily release iron at lower pH levels, indicating it may function more in iron storage or buffering than transport. Its unique structure includes extensive glycosylation and a GPI anchor that localizes it to the cell surface, where it may participate in iron metabolism and signaling functions.

Functionally, MELTF is implicated in iron homeostasis, potentially protecting cells from iron-mediated toxicity, while also supporting cancer cell proliferation, migration, and angiogenesis. It is overexpressed in various cancers, making it a potential biomarker and therapeutic target. Additionally, elevated MELTF levels in neurodegenerative diseases suggest it could contribute to iron-related neurodegeneration or serve a protective role in neuronal iron homeostasis.

In summary, MELTF’s complex role in iron handling, cancer biology, and neuroprotection highlights its significance in both normal physiology and disease. Further understanding of MELTF’s functions could reveal new therapeutic opportunities for treating cancers, neurodegenerative diseases, and disorders of iron metabolism.