Recombinant Human Leucine-rich repeat-containing protein 8E (LRRC8E)
Description
Introduction to Recombinant Human Leucine-rich repeat-containing protein 8E (LRRC8E)
Recombinant Human Leucine-rich repeat-containing protein 8E (LRRC8E) is a subunit of the volume-regulated anion channel (VRAC) family, which plays a crucial role in maintaining cellular homeostasis by regulating cell volume and membrane potential. The LRRC8 family includes five subunits (LRRC8A-E), each contributing to the diverse functions of VRACs in various cellular processes.
Role in Organic Compound Transport
LRRC8E is particularly noted for its ability to facilitate the transport of negatively charged organic compounds. In contrast, LRRC8D supports the transport of both negatively charged and neutral compounds . This specificity highlights the importance of subunit composition in determining the functional properties of VRACs.
Research Findings
Recent studies have emphasized the significance of LRRC8 subunits in forming functional VRACs. For example, sequential co-immunoprecipitation experiments have confirmed that VRACs can contain multiple LRRC8 subunits, including LRRC8E . Additionally, the role of LRRC8 proteins in immune cell function and cancer progression has been explored, though specific studies on LRRC8E are less prevalent compared to LRRC8A .
Table 1: LRRC8 Subunits and Their Functions
Table 2: Expression and Role in Cancer
Future Research Directions
While LRRC8E's role in VRAC function is established, further research is needed to fully understand its structural and functional contributions. Investigating the specific interactions between LRRC8E and other subunits could provide insights into developing targeted therapies for conditions where VRACs play a critical role.
Product Specs
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Target Background
Q&A
What is LRRC8E and how does it contribute to VRAC functionality?
LRRC8E (Leucine-rich repeat-containing protein 8E) is one of five LRRC8 family proteins (LRRC8A-E) that form heteromeric volume-regulated anion channels (VRACs). While LRRC8A is the essential subunit for VRAC formation, LRRC8E is an auxiliary subunit that confers specific functional properties to the channel complex .
VRACs are crucial for regulating cell volume by transporting chloride ions and various organic osmolytes across the plasma membrane in response to osmotic challenges . The incorporation of LRRC8E into heteromeric channel complexes with LRRC8A creates channels with distinct permeability profiles and regulatory properties, particularly regarding oxidation sensitivity .
What is the molecular structure of LRRC8E?
Like other LRRC8 family members, LRRC8E has a modular structure comprising four principal domains:
The quaternary structure of LRRC8-containing VRACs varies, with evidence suggesting hexameric or heptameric assemblies . Cryo-EM studies have revealed that the LRRDs can adopt multiple conformational arrangements, contributing to channel function diversity .
What is the tissue distribution pattern of LRRC8E?
LRRC8E shows a specific tissue distribution pattern that differs from other LRRC8 family members:
This distribution pattern suggests tissue-specific roles for LRRC8E-containing VRACs, particularly in immune and respiratory functions .
How do oxidative conditions specifically affect LRRC8A/LRRC8E heteromers?
One of the most distinctive properties of LRRC8E-containing channels is their unique response to oxidative conditions:
This dramatic differential response suggests that LRRC8E-containing VRACs may have specialized functions in conditions involving oxidative stress or redox signaling . The molecular basis for this unique activation involves specific cysteine residues, though the precise positioning and mechanism remain to be fully elucidated.
What are the permeability characteristics of LRRC8E-containing channels?
LRRC8E incorporation confers specific permeability properties to VRAC channels:
These permeability differences suggest that the subunit composition of VRAC channels allows for fine-tuning of osmolyte release based on specific cellular needs .
How does LRRC8E contribute to immune function?
LRRC8E plays a specialized role in immune signaling through cGAMP transport:
This immune-related function represents a specialized role for LRRC8E beyond simple volume regulation and suggests its importance in host defense mechanisms .
What experimental approaches can be used to study LRRC8E function?
When implementing these approaches, researchers should consider the native heteromeric composition of VRAC channels and design experiments that account for potential variations in subunit stoichiometry and arrangement .
How can specific domains of LRRC8E be targeted for functional studies?
Domain-specific targeting can reveal crucial structure-function relationships:
These approaches have revealed that even seemingly minor changes in specific domains can substantially alter channel function, highlighting the precise structural basis of LRRC8E functionality .
What is known about LRRC8E involvement in disease states?
Understanding LRRC8E's role in these pathophysiological contexts may provide new therapeutic targets for conditions involving volume dysregulation, oxidative stress, or immune dysfunction .
How might the unique oxidation sensitivity of LRRC8E be exploited therapeutically?
The distinctive activation of LRRC8A/E heteromers by oxidation offers potential therapeutic applications:
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Targeting methodology: Develop compounds that specifically modulate LRRC8E-containing channels without affecting other LRRC8 heteromers .
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Experimental approach: Use sybody technology to develop synthetic nanobodies that bind to distinct epitopes of the LRR domain, as these have been shown to either inhibit or enhance channel activity .
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Potential applications:
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Modulate cellular responses to oxidative stress
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Regulate immune signaling through cGAMP transport
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Intervene in pathological processes involving aberrant VRAC activity
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Considerations: The tissue-specific expression pattern of LRRC8E (high in lung and spleen) provides opportunity for targeted interventions in respiratory and immune disorders .
What are the key unresolved questions regarding LRRC8E function?
Several important aspects of LRRC8E biology remain to be fully elucidated:
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Stoichiometry and arrangement: What is the precise subunit ratio and spatial arrangement of LRRC8E in heteromeric VRAC assemblies?
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Oxidation mechanism: Which specific cysteine residues are responsible for the unique oxidation sensitivity of LRRC8A/E heteromers?
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Regulatory interactions: What protein-protein interactions and post-translational modifications regulate LRRC8E function?
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Physiological roles: What are the specific physiological functions of LRRC8E-containing VRACs in tissues with high expression levels?
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Pathological significance: How do alterations in LRRC8E contribute to human disease states?
Addressing these questions will require integrative approaches combining structural biology, electrophysiology, cell biology, and in vivo models.
What emerging technologies might advance LRRC8E research?
These approaches will help resolve the considerable heterogeneity in VRAC composition and function, leading to more precise understanding of LRRC8E's specialized roles.
