SERPINF1 - serpin family F member 1 |Elisa - Clia - Antibody - Protein

Background

SERPINF1, also known as pigment epithelium-derived factor (PEDF), is a member of the serpin (serine protease inhibitor) family, though it has unique properties distinct from classical serpins. Unlike most serpins, SERPINF1 does not function as a typical protease inhibitor but is instead a multifunctional protein with potent anti-angiogenic, neuroprotective, and anti-inflammatory effects. First identified in the pigment epithelium of the eye, it has since been found in a variety of tissues and is now recognized as a crucial player in many biological processes, including the inhibition of abnormal blood vessel growth and tissue protection.

SERPINF1 is highly expressed in the eye, particularly in the retinal pigment epithelium (RPE) and other neural tissues. It is most famous for its role in ocular health, but its functions extend to other organs, such as the liver, heart, skin, and brain. Mutations in the SERPINF1 gene are associated with several diseases, most notably osteogenesis imperfecta (OI) type VI, a genetic disorder affecting bone formation.

Protein Structure

SERPINF1 is a glycoprotein of approximately 50 kDa, composed of 418 amino acids. Its structure is typical of the serpin superfamily, featuring a conserved serpin fold with a central β-sheet and surrounding α-helices. However, unlike classical serpins, SERPINF1 lacks the critical reactive center loop (RCL) that is necessary for serine protease inhibition. This structural difference underlies its inability to function as a protease inhibitor and instead allows it to exert non-inhibitory functions, particularly in angiogenesis and neuroprotection.

The tertiary structure of SERPINF1 includes regions critical for receptor binding and interaction with extracellular matrix components. One of the key functional regions of the protein is a heparin-binding site, which allows SERPINF1 to associate with the extracellular matrix and modulate cell signaling. It also contains multiple receptor-binding sites that enable its interaction with various cell surface receptors, including integrins and lipoprotein receptors, which mediate its diverse biological effects.

Classification and Subtypes

SERPINF1 belongs to the clade F of the serpin superfamily. Although it shares the characteristic serpin fold, it does not function as a classical serine protease inhibitor. Instead, SERPINF1 exerts its effects primarily through interactions with cell surface receptors and extracellular matrix components.

There are no known subtypes of SERPINF1, but mutations in the SERPINF1 gene can lead to distinct clinical phenotypes. These mutations typically result in a loss of SERPINF1 function, leading to diseases like osteogenesis imperfecta type VI, where the lack of functional SERPINF1 impairs bone mineralization and leads to brittle bones.

Function and Biological Significance

SERPINF1 is a multifunctional protein with diverse biological activities, making it a critical player in several physiological processes. Some of its key functions include:

1. Anti-Angiogenic Activity: One of the most well-known functions of SERPINF1 is its potent anti-angiogenic activity. It inhibits the growth of new blood vessels (angiogenesis) by binding to and antagonizing receptors involved in endothelial cell proliferation and migration. This property is particularly important in the eye, where abnormal blood vessel growth can lead to vision loss, as seen in diseases like age-related macular degeneration (AMD) and diabetic retinopathy. SERPINF1's ability to inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis makes it a natural counterbalance to pro-angiogenic factors in the eye and other tissues.
2. Neuroprotective Function: SERPINF1 is also known for its neuroprotective properties. It promotes the survival of neurons and other neural cells by inhibiting apoptosis and oxidative stress. This function is especially critical in the retina, where SERPINF1 protects photoreceptors and other retinal cells from degeneration. It has been proposed as a potential therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, due to its ability to protect against neuronal damage.
3. Anti-Inflammatory Effects: In addition to its anti-angiogenic and neuroprotective functions, SERPINF1 has anti-inflammatory properties. It modulates immune cell activity and inhibits the production of pro-inflammatory cytokines, helping to reduce tissue damage during inflammation. This anti-inflammatory role is particularly relevant in chronic inflammatory diseases, where uncontrolled inflammation can lead to tissue destruction.
4. Bone Mineralization: Mutations in the SERPINF1 gene have been linked to osteogenesis imperfecta type VI, a rare genetic disorder characterized by defective bone formation. In individuals with this disorder, the absence of functional SERPINF1 impairs proper bone mineralization, leading to brittle bones and frequent fractures. This highlights the importance of SERPINF1 in bone homeostasis, although the precise mechanisms by which it influences bone formation remain an area of active research.
5. Cancer: SERPINF1 has also been studied in the context of cancer, where its ability to inhibit angiogenesis may suppress tumor growth and metastasis. By preventing the formation of new blood vessels, SERPINF1 can limit the supply of nutrients to tumors, thereby restricting their growth. In some cancers, reduced expression of SERPINF1 is associated with more aggressive disease and poorer outcomes, suggesting that it may have tumor-suppressive properties.

Clinical Issues

The most well-established clinical condition associated with SERPINF1 mutations is osteogenesis imperfecta type VI. Patients with this disorder have mutations that result in a loss of SERPINF1 function, leading to severe bone fragility, frequent fractures, and impaired bone healing. Unlike other forms of osteogenesis imperfecta, type VI is characterized by a mineralization defect that results in bones that are less dense and more prone to fractures.

SERPINF1 has also been implicated in several other diseases, including:

1. Eye Diseases: Given its role in inhibiting angiogenesis, SERPINF1 is of great interest in the treatment of ocular diseases characterized by abnormal blood vessel growth, such as age-related macular degeneration (AMD) and diabetic retinopathy. Therapies that increase SERPINF1 levels or mimic its activity may help to prevent vision loss in these conditions.
2. Cancer: Reduced expression of SERPINF1 has been observed in some cancers, where it may contribute to tumor progression by allowing unchecked angiogenesis and tumor growth. Conversely, increased SERPINF1 expression may have therapeutic potential in limiting tumor angiogenesis and metastasis.
3. Neurodegenerative Diseases: Due to its neuroprotective properties, SERPINF1 has been explored as a potential therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. By protecting neurons from apoptosis and oxidative stress, SERPINF1 may help to slow the progression of these diseases and preserve cognitive function.

Summary

SERPINF1, also known as pigment epithelium-derived factor (PEDF), is a multifunctional protein with key roles in inhibiting angiogenesis, protecting neurons, and regulating inflammation. Although it belongs to the serpin superfamily, it does not act as a classical protease inhibitor but instead exerts its effects through interactions with cell surface receptors and extracellular matrix components. Mutations in the SERPINF1 gene are associated with osteogenesis imperfecta type VI, a rare genetic disorder that affects bone mineralization.

In addition to its role in bone homeostasis, SERPINF1 is a critical regulator of ocular health, where it helps to prevent abnormal blood vessel growth in diseases like age-related macular degeneration and diabetic retinopathy. Its neuroprotective and anti-inflammatory properties make it a potential therapeutic target for neurodegenerative diseases and chronic inflammatory conditions. Finally, SERPINF1's ability to inhibit angiogenesis also makes it an important factor in cancer biology, where it may help to suppress tumor growth and metastasis.