SEMA7A - semaphorin 7A | Elisa - Clia - Antibody - Protein

Background

Semaphorin 7A (SEMA7A) is a membrane-associated protein that belongs to the semaphorin family, a group of proteins widely recognized for their roles in axon guidance, immune response, and cellular signaling. Semaphorins, initially identified as axon-guidance molecules, are now understood to function across a variety of biological systems, impacting cell-cell interactions, cell migration, and immune cell regulation. SEMA7A, also referred to as CD108, is distinct from other semaphorins due to its glycophosphatidylinositol (GPI) anchorage, allowing it to localize on the cell surface and interact with various receptors.

SEMA7A is broadly expressed in a range of tissues, including the nervous system, immune cells, skin, and certain cancer types. It is known to participate in axonal guidance, immune regulation, bone development, and pathological conditions, such as tumorigenesis and fibrotic diseases. One of its key functions is promoting axonal outgrowth and guiding neural connections, mediated through its interactions with integrins and other receptors. Furthermore, SEMA7A is actively involved in inflammatory and immune responses, modulating immune cell migration, adhesion, and activation. This diversity in function makes SEMA7A a molecule of interest in fields ranging from neurobiology to immunology and oncology.

Protein Structure

SEMA7A is approximately 666 amino acids in length with a molecular weight around 75 kDa. The structure of SEMA7A is characterized by distinctive features that allow it to interact with various cell surface receptors, contributing to its roles in cell signaling, adhesion, and migration.

Semaphorin (Sema) Domain:

• The Sema domain, a conserved domain within the semaphorin family, spans approximately the first 500 amino acids. This domain is critical for binding to receptors and mediating signal transduction pathways. It forms a seven-bladed β-propeller structure that facilitates interactions with other molecules, particularly integrins.
• Within the Sema domain, SEMA7A contains conserved cysteine residues that stabilize the structure and contribute to ligand binding specificity.

Immunoglobulin-like (Ig) Domain:

• Following the Sema domain is an Ig-like domain. This domain is a structural motif involved in protein-protein interactions and contributes to the overall stability and functionality of the protein.
• The Ig domain in SEMA7A enables interaction with other cell surface molecules, promoting intercellular adhesion and communication.

GPI Anchor:

• Unlike most other semaphorins, SEMA7A is anchored to the cell surface by a glycophosphatidylinositol (GPI) moiety. The GPI anchor enables SEMA7A to associate with the outer leaflet of the cell membrane while retaining mobility along the cell surface. This anchor structure is crucial for the protein's ability to engage in close-range signaling with adjacent cells.
• GPI-anchoring provides SEMA7A with increased membrane flexibility and the potential for rapid localization to different cell regions, facilitating dynamic cell-cell interactions and signaling events.

Classification and Subtypes

SEMA7A is part of the semaphorin family, a diverse group of proteins categorized into eight classes based on sequence similarity and structural characteristics. Specifically, SEMA7A falls under the Class VII Semaphorin subgroup. It is unique in that it is the only known GPI-anchored semaphorin, while other semaphorins are typically transmembrane or secreted proteins. Due to its unique anchoring, SEMA7A can be readily released from the cell surface, a characteristic that enables it to participate in autocrine and paracrine signaling.

There are no widely recognized subtypes of SEMA7A. However, the protein can undergo post-translational modifications, such as glycosylation and phosphorylation, which may influence its functional diversity.

Function and Biological Significance

SEMA7A performs a range of functions in different cellular environments:

Axon Guidance and Neural Development:

• SEMA7A plays a significant role in axon guidance by interacting with neuronal receptors, specifically integrins, to influence axonal outgrowth and directional cues. Its primary action involves promoting axonal extension and adhesion to surrounding tissues, supporting the development of neural circuits.
• In the brain, SEMA7A has been found to impact both the growth and orientation of dendrites, facilitating neuronal connectivity and plasticity, critical processes for proper nervous system development.

Immune Regulation:

• SEMA7A is implicated in the regulation of immune responses. It is expressed on various immune cells, including T cells and monocytes, where it modulates cell activation, cytokine production, and immune cell migration.
• Through its interaction with the plexin C1 receptor on monocytes and other immune cells, SEMA7A can trigger pro-inflammatory responses, such as the release of cytokines including TNF-α and IL-6. This activity positions SEMA7A as a key molecule in immune surveillance and inflammatory responses.
• SEMA7A is also involved in the recruitment and adhesion of immune cells to inflamed tissues, promoting a targeted immune response.

Bone Development and Remodeling:

• SEMA7A has been shown to influence osteoblast differentiation and bone formation. Its expression on osteoblasts (bone-forming cells) suggests a role in bone development and remodeling.
• Studies indicate that SEMA7A can stimulate osteoblast activity by enhancing cell adhesion and migration, thereby contributing to bone density maintenance and repair.

Angiogenesis and Tumor Progression:

• In cancer biology, SEMA7A has been found to participate in tumor angiogenesis and metastasis. Its expression is elevated in several cancer types, including melanoma and breast cancer, where it promotes the migration and invasion of tumor cells.
• SEMA7A’s interaction with integrins on endothelial and tumor cells facilitates angiogenesis, enhancing the blood supply to tumors and supporting tumor growth. As such, SEMA7A has been identified as a potential therapeutic target in anti-cancer strategies aimed at inhibiting tumor vascularization and spread.

Role in Fibrosis and Tissue Repair:

• SEMA7A plays a part in wound healing and fibrosis by promoting the migration of fibroblasts to injured tissues, aiding tissue repair processes. However, excessive SEMA7A activity has been linked to fibrosis, as seen in lung and liver tissues, where it drives chronic inflammation and tissue scarring.
• Through its signaling interactions, SEMA7A influences fibroblast differentiation and matrix deposition, central to fibrosis pathology.

Clinical Issues

Cancer:

• SEMA7A expression is associated with the progression of several types of cancer. In breast cancer and melanoma, high levels of SEMA7A are correlated with increased tumor invasiveness and metastatic potential. Its role in promoting angiogenesis further supports tumor growth, making SEMA7A a potential marker for cancer progression and a target for therapeutic intervention.

Autoimmune and Inflammatory Diseases:

• Given its pro-inflammatory role, SEMA7A is implicated in autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Elevated SEMA7A expression on immune cells can exacerbate inflammation and tissue damage in these diseases. In MS, SEMA7A is involved in T cell-mediated damage to the central nervous system (CNS).
• Blocking SEMA7A activity may present a therapeutic approach in these conditions by reducing immune cell recruitment and dampening inflammation.

Fibrotic Diseases:

• SEMA7A is a contributor to the pathology of fibrotic diseases, including idiopathic pulmonary fibrosis and hepatic fibrosis. Its upregulation in fibroblasts enhances collagen deposition and matrix formation, contributing to fibrosis.
• Targeting SEMA7A in fibrotic diseases could help alleviate excessive tissue scarring and improve organ function.

Neurological Disorders:

• Given its role in axon guidance, SEMA7A is associated with neurodevelopmental and neurodegenerative disorders. Abnormal SEMA7A signaling has been linked to conditions like schizophrenia and Alzheimer’s disease, where dysregulated axonal connections and immune responses may play roles in disease pathology.

Summary

SEMA7A (Semaphorin 7A) is a multifunctional GPI-anchored glycoprotein within the semaphorin family that plays pivotal roles in neuronal guidance, immune regulation, and tissue remodeling. Structurally, it features a conserved Sema domain and an Ig-like domain, which facilitate its interactions with receptors such as integrins and plexins. SEMA7A’s GPI anchor enables membrane localization and rapid signaling in processes including axonal outgrowth, immune cell activation, and fibroblast migration.

Functionally, SEMA7A is crucial in the development and maintenance of neuronal circuits, immune responses, and bone structure. It also participates in pathological processes such as cancer progression, fibrosis, and autoimmune disease. Elevated levels of SEMA7A are associated with poor outcomes in cancer, fibrotic diseases, and inflammatory conditions, making it a potential biomarker and therapeutic target for these diseases.