SLC7A5 - solute carrier family 7 member 5 |Elisa - Clia - Antibody - Protein

Background

SLC7A5, also known as LAT1 (L-type amino acid transporter 1), is a transmembrane protein crucial for amino acid transport across the plasma membrane. It is part of the solute carrier family 7 (SLC7), specifically associated with the transport of large neutral amino acids (LNAAs) like leucine, isoleucine, valine, phenylalanine, and tryptophan, which are essential for various cellular functions. LAT1 is a high-affinity, sodium-independent transporter and functions as part of a heteromeric complex with SLC3A2 (4F2hc or CD98), which acts as a chaperone protein for the proper membrane localization and functionality of LAT1.

SLC7A5 plays a significant role in cellular growth and proliferation, and it is highly expressed in rapidly dividing cells. It is abundant in tissues with high metabolic demands, such as the brain, placenta, and certain immune cells, as well as in many cancer cell types, where it facilitates the increased amino acid demand required for protein synthesis and tumor growth. LAT1 is also integral to the blood-brain barrier, as it enables the transport of essential amino acids into the brain, thereby impacting neurotransmitter synthesis.

Protein Structure

The SLC7A5 protein has a unique structure within the solute carrier family, with approximately 507 amino acids. It is a multi-pass membrane protein with multiple transmembrane domains that facilitate its function as an amino acid transporter. The structural details of SLC7A5 are as follows:

Transmembrane Domains:

• SLC7A5 contains 12 transmembrane helices arranged within the plasma membrane. These helices form a channel-like structure enabling amino acid transport across the membrane. The amino acid binding sites within these transmembrane regions recognize large, hydrophobic amino acids, ensuring the transporter’s specificity.
• The transmembrane regions contain hydrophobic amino acids essential for the protein's integration into the lipid bilayer and interact with the lipid components of the membrane, stabilizing LAT1’s orientation within the membrane.

Extracellular and Intracellular Loops:

• SLC7A5’s transmembrane helices are connected by short extracellular and intracellular loops, allowing flexibility within the structure. These loops are likely involved in conformational changes necessary for amino acid transport.

Heterodimerization with SLC3A2 (4F2hc):

• SLC7A5 requires association with the SLC3A2 protein for stability and transport activity. This interaction forms a heterodimeric transporter complex with SLC3A2, which acts as a chaperone. The SLC3A2 subunit is a single-pass transmembrane protein with an extracellular domain essential for proper membrane localization and functional conformation of LAT1.
• This heterodimer formation is mediated by a covalent disulfide bond, facilitating the functional transport of amino acids across the cell membrane.

Substrate Binding Site:

• The substrate-binding pocket is located within the transmembrane domains, allowing SLC7A5 to accommodate large neutral amino acids. This specificity arises from the size and hydrophobicity of the binding site, which selectively permits the passage of LNAAs.

Classification and Subtypes

SLC7A5 belongs to the solute carrier family 7 (SLC7) and falls under the LAT (L-type amino acid transporter) subfamily. LAT transporters are essential for amino acid uptake and exchange, enabling cells to maintain proper amino acid homeostasis. Although SLC7A5 itself does not have distinct subtypes, it functions in association with various chaperone proteins within the SLC7 family, primarily with SLC3A2. Together, the SLC7 family members regulate amino acid influx and efflux, directly influencing cellular metabolism and signaling pathways in tissues with high metabolic activity.

Function and Biological Significance

Amino Acid Transport:

• SLC7A5’s primary function is the transport of large neutral amino acids across the cell membrane. By mediating the influx of essential amino acids, SLC7A5 contributes to protein synthesis, cellular growth, and metabolic regulation.
• As a sodium-independent exchanger, SLC7A5 facilitates amino acid transport using a bidirectional mechanism. It exchanges extracellular LNAAs, such as leucine, with intracellular amino acids like glutamine. This exchange plays a critical role in maintaining cellular amino acid balance.

Role in mTOR Signaling:

• SLC7A5 is directly involved in activating the mTORC1 (mechanistic target of rapamycin complex 1) signaling pathway, a central regulator of cellular growth and metabolism. By importing leucine and other essential amino acids, SLC7A5 triggers mTORC1 activation, promoting anabolic processes such as protein synthesis and cell proliferation.
• This function is particularly relevant in cancer cells, which often overexpress LAT1 to meet the high amino acid demands necessary for rapid growth and division. The upregulation of SLC7A5 in cancer enhances mTOR signaling, making LAT1 a potential therapeutic target in cancer treatments.

Blood-Brain Barrier:

• SLC7A5 is highly expressed in endothelial cells of the blood-brain barrier, where it facilitates the transport of essential amino acids into the brain. These amino acids are precursors for neurotransmitters such as dopamine and serotonin, impacting cognitive function and mood regulation.
• The transporter’s function at the blood-brain barrier is crucial for maintaining neuronal health and proper brain function. Disruptions in SLC7A5 activity can lead to neurological disorders, as the brain relies on LAT1 to supply critical precursors for neurotransmitter synthesis.

Immune Function:

• SLC7A5 is also expressed on activated immune cells, where it supports cellular proliferation and cytokine production by importing essential amino acids. Immune cells upregulate LAT1 in response to activation signals, enabling these cells to meet increased metabolic demands during immune responses.

Clinical Issues

Cancer:

• SLC7A5 is overexpressed in various cancers, including breast, lung, and prostate cancer. Its upregulation supports the metabolic requirements of cancer cells, enhancing mTORC1 activation and contributing to uncontrolled proliferation.
• Due to its role in tumor growth and metastasis, LAT1 has emerged as a target for cancer therapy. Inhibitors of SLC7A5 are being explored as a means to reduce amino acid availability in tumors, thereby inhibiting tumor growth and sensitizing cancer cells to other treatments.

Neurological Disorders:

• Mutations in SLC7A5 are associated with certain neurological disorders, including autism spectrum disorders and intellectual disability. Defective amino acid transport across the blood-brain barrier disrupts neurotransmitter synthesis, leading to neurodevelopmental abnormalities.
• Deficiencies in LAT1 function can lead to altered levels of neurotransmitters in the brain, impacting mood, cognition, and behavior. Researchers are investigating LAT1 modulators that may potentially restore amino acid balance in patients with LAT1-related neurological disorders.

Immune Dysregulation:

• Given SLC7A5’s role in immune cell activation, dysregulation of LAT1 function may impact immune responses. LAT1 inhibition could potentially suppress immune cell proliferation and cytokine release, which has implications in autoimmune diseases and inflammatory conditions.

Metabolic Disorders:

• SLC7A5 has potential involvement in metabolic disorders due to its role in amino acid metabolism. Impaired LAT1 function can lead to metabolic imbalances, affecting energy homeostasis and cellular growth. There is ongoing research exploring LAT1 as a metabolic target, with applications in treating obesity and diabetes.

Summary

SLC7A5, or LAT1, is a crucial amino acid transporter in the solute carrier family that facilitates the uptake of large neutral amino acids across the plasma membrane. Its structure includes 12 transmembrane domains, flexible loops, and an interaction with SLC3A2 (4F2hc), which aids in stabilizing and activating LAT1. Functionally, SLC7A5 is involved in amino acid transport, cellular growth, mTORC1 signaling, blood-brain barrier maintenance, and immune function. Overexpression of SLC7A5 in cancer underscores its importance in tumor metabolism, making it a target for cancer therapy. In the central nervous system, SLC7A5 is integral to neurotransmitter synthesis, while its role in the immune system impacts immune responses during infections and inflammation. Disruptions in LAT1 function are implicated in various clinical conditions, including cancer, neurological disorders, immune dysregulation, and metabolic diseases.