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LRRC8A Membrane Protein Introduction

Introduction of LRRC8A

LRRC8A (also known as SWELL1) is a member of the LRRC8 protein family, which is found exclusively in vertebrates and encoded by the LRRC8A gene. LRRC8A is recently shown to be an essential component of volume-regulated anion channel (VRAC) since knockdown or deletion of SWELL1 can abolish ICl swell. LRRC8A is conserved across vertebrate species, and four additional homologous family members (LRRC8B-E) are usually present in their genomes. Deletion and rescue studies have shown that functional VRAC requires LRRC8A and at least one other LRRC8 subunit in heterologous systems, which has revealed subunit interactions by co-immunoprecipitation.

Basic Information of LRRC8A
Protein Name Volume-regulated anion channel subunit LRRC8A
Gene Name LRRC8A
Aliases Leucine-rich repeat-containing protein 8A, Swelling protein 1
Organism Homo sapiens (Human)
UniProt ID Q8IWT6
Transmembrane Times 4
Length (aa) 810
Sequence MIPVTELRYFADTQPAYRILKPWWDVFTDYISIVMLMIAVFGGTLQVTQDKMICLPCKWVTKDSCNDSFRGWAAPGPEPTYPNSTILPTPDTGPTGIKYDLDRHQYNYVDAVCYENRLHWFAKYFPYLVLLHTLIFLACSNFWFKFPRTSSKLEHFVSILLKCFDSPWTTRALSETVVEESDPKPAFSKMNGSMDKKSSTVSEDVEATVPMLQRTKSRIEQGIVDRSETGVLDKKEGEQAKALFEKVKKFRTHVEEGDIVYRLYMRQTIIKVIKFILIICYTVYYVHNIKFDVDCTVDIESLTGYRTYRCAHPLATLFKILASFYISLVIFYGLICMYTLWWMLRRSLKKYSFESIREESSYSDIPDVKNDFAFMLHLIDQYDPLYSKRFAVFLSEVSENKLRQLNLNNEWTLDKLRQRLTKNAQDKLELHLFMLSGIPDTVFDLVELEVLKLELIPDVTIPPSIAQLTGLKELWLYHTAAKIEAPALAFLRENLRALHIKFTDIKEIPLWIYSLKTLEELHLTGNLSAENNRYIVIDGLRELKRLKVLRLKSNLSKLPQVVTDVGVHLQKLSINNEGTKLIVLNSLKKMANLTELELIRCDLERIPHSIFSLHNLQEIDLKDNNLKTIEEIISFQHLHRLTCLKLWYNHIAYIPIQIGNLTNLERLYLNRNKIEKIPTQLFYCRKLRYLDLSHNNLTFLPADIGLLQNLQNLAITANRIETLPPELFQCRKLRALHLGNNVLQSLPSRVGELTNLTQIELRGNRLECLPVELGECPLLKRSGLVVEEDLFNTLPPEVKERLWRADKEQA

Function of LRRC8A Membrane Protein

The LRRC8 protein forms a heteromeric channel that is important both in structure and function, while VRAC is formed with LRRC8A and other LRRC8 paralogs. VRACs are heteromers consisted of up to five different LRRC8 proteins, with LRRC8A being the only essential subunit. The LRRC8 protein has important structural/functional significance. Specifically, the formation of VRAC requires a protein region of LRRC8A and a protein region of other LRRC8 paralogs. Deletion of LRRC8A abolishes VRAC’s transport of halide anions and a plethora of organic compounds. Truncated LRRC8A mutants are largely stuck in the ER, where they are unable to carry the other LRRC8 subunits (B-E) to the plasma membrane. The truncation of LRRC8A in ébouriffé mice thus results in drastically reduced, but not completely abolished, swelling-activated ICl, vol currents.

Superposition of subunits of LRRC8A (green) and connexin Cx26 (red, left) and expanded view of the ESD (right). Selected secondary structure elements are indicated. Fig.1 Superposition of subunits of LRRC8A (green) and connexin Cx26 (red, left) and expanded view of the ESD (right). Selected secondary structure elements are indicated. (Deneka, 2018)

Application of LRRC8A Membrane Protein in Literature

  1. Formaggio F., et al. LRRC8A is essential for swelling-activated chloride current and for regulatory volume decrease in astrocytes. Faseb journal. 2018. PubMed ID: 29957062

    This article finds that LRRC8A is an essential subunit of VRAC and a key factor for astroglial volume homeostasis.

  2. Yamada T., et al. Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function. Journal of general physiology. 2018, 150(7):1003-1015. PubMed ID: 29853476

    This paper demonstrates that LRRC8C, LRRC8D or LRRC8E, LRRC8A IL and EL1 are critical for the formation and function of VRAC and provides new insights into channel structure and regulation.

  3. Deneka D., et al. Structure of a volume-regulated anion channel of the LRRC8 family. Nature. 2018, 558(7709):254-259. PubMed ID: 29769723

    This article reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

  4. Stauber T. The volume-regulated anion channel is formed by LRRC8 heteromers - molecular identification and roles in membrane transport and physiology. Biological Chemistry. 2015, 396(9-10):975-90. PubMed ID: 25868000

    This review summarizes the identification of LRRC8 heteromers as VRAC components, and describes the similarities between LRRC8 protein and pannexins, and discusses whether VRAC performs greater osmotic pressure.

  5. Gradogna A., et al. Subunit dependent oxidative stress sensitivity of LRRC8 volume regulated anion channels. Journal of Physiology. 2017, 595(21):6719-6733. PubMed ID: 28841766

    This article shows that LRRC8 channels are directly modulated by oxidation in a subunit-dependent manner.

LRRC8A Preparation Options

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Reference

  1. Deneka D, et al. (2018). Structure of a volume-regulated anion channel of the LRRC8 family. Genes & development. 558(7709):254-259.

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