MLC1 Membrane Protein Introduction

Introduction of MLC1

Membrane protein MLC1, encoded by the MLC1 gene, contains eight putative transmembrane domains and short amino- and carboxylic-cytoplasmic terminals. The human MLC1 gene encodes a membrane protein consisting of 377 amino acids, which is predicted to have eight transmembrane domains with very low homology to voltage-dependent potassium (K⁺) channel subunits. In human brain, MLC1 is expressed in astrocyte end-foot processes, ependymal cells lining the ventricles and Bergmann glia in the cerebellum. The high expression of MLC1 in brain astrocytes contacting blood vessels and meninges and brain alterations observed in MLC patients suggests a role of MLC1 in the regulation of ion and water homeostasis. Recent studies have shown that MLC1 establishes structural and/or functional interactions with several ion/water channels and ion transporters.

Function of MLC1 Membrane Protein

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare hereditary autosomal recessive form of childhood spongiform white matter dystrophy caused by a mutation in the MLC1 gene. MLC1 is expressed in astrocytes (but not in oligodendrocytes) and myelin-forming cells, and in brain damages consistent with fluid balance alterations in the brain of MLC patients, suggesting that MLC pathogenesis might result from astrocyte dysfunction in the maintenance of extracellular fluid homeostasis. Due to similarities in brain damages observed in MLC patients and in patients affected by congenital muscular dystrophy with brain involvement, a relationship between MLC1 and the dystrophin-associated glycoprotein complex (DGC) has been suggested. This multiprotein complex is mainly expressed in muscle tissue but also in astrocytes and neurons where it plays a role in brain development and in the regulation of ion and fluid homeostasis.

Fig.1 Interactions between MCL-1 and BH3. (a) NMR structure of unbound MCL-1171-327. (b) X-ray structure of MCL-1172-327 in complex with a BH3 helical peptide (green). (Konermann, 2016)

Application of MLC1 Membrane Protein in Literature

1. Brignone M.S., et al. MLC1 protein: a likely link between leukodystrophies and brain channelopathies. Frontiers in Cellular Neuroscience. 2015, 9: 66. PubMed ID: 25883547
   
   

   This article reviews data on the functional properties of MLC1 obtained in vitro and in vivo models and discusses the effects of MLC1 mutations on the brain-channel disease.

2. Lanciotti A., et al. MLC1 trafficking and membrane expression in astrocytes: role of caveolin-1 and phosphorylation. Neurobiology of Disease. 2010, 37(3): 581-95. PubMed ID: 19931615
   
   

   This article demonstrates that MLC1 is also expressed in intracellular vesicles and endoplasmic reticulum and undergoes caveolae/raft-mediated endocytosis.

3. Toutounchian J.J., et al. Selective expression of eGFP in mouse perivascular astrocytes by modification of the Mlc1 gene using T2A-based ribosome skipping. Genesis. 2017, 55(10). PubMed ID: 28929580
   
   

   This article suggests that Mlc1-eGFP knock-in mice can be used to identify perivascular astrocytes in the brain and retina and describes how these cell types regulate cerebrovascular function in health and disease.

4. Sirisi S., et al. Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes: implications in megalencephalic leukoencephalopathy. Human Molecular Genetics. 2017, 26(13): 2436-2450. PubMed ID: 28398517
   
   

   This article proposes that GlialCAM/MLC1/ClC-2 mediated chloride influx in astrocytes may be required to compensate for excess potassium, and this compensatory deficiency may help to study the pathogenesis of MLC disease.

5. Wang J., et al. Identification of novel MLC1 mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC). Journal of Human Genetics. 2011, 56(2): 138-42. PubMed ID: 21160490
   
   

   This study shows a unique MLC1 mutation profile in Chinese MLC patients, which should be systematically studied to assess mutation profiles in different populations.

MLC1 Preparation Options

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Reference

1. Konermann L. (2016). Heavy lessons in protein allostery. Nature Structural & Molecular Biology. 23(6): 511.

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