Transmembrane topology and oligomeric nature of an astrocytic membrane protein, MLC1

Hwang, Junmo; Park, Kunwoong; Lee, Ga-Young; Yoon, Bo Young; Kim, Hyunmin; Roh, Sung Hoon; Lee, Byoung-Cheol; Kim, Kipom; Lim, Hyun–Ho

doi:10.1098/rsob.210103

Cited by 5 publications

(5 citation statements)

References 65 publications

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“…Thus, MLC1 sequence identity analysis by BLAST/PSI-BLAST algorithm identified the voltage gated potassium channel Kv1.1 alpha subunit (KCNA1) as the protein with the highest sequence identity (less than 20% amino acid identity) [ 23 ], suggesting that MLC1 could act as an ion channel. In agreement with this hypothesis, it is known that MLC1 can form homo-oligomers, a characteristic found in many ion channels proteins [ 24 ]. Moreover, MLC patients may present epileptic seizures, which is a common feature in ion channel diseases, but not in leukodystrophies [ 25 ].…”

Section: Novel Insights Into Glialcam/mlc1 Function By Alphafold Stru...mentioning

confidence: 58%

“…As MLC1 mutations have been reported to cause protein instability, which consequently causes its degradation at the endoplasmic reticulum or lysosomes [ 29 , 30 , 31 ], we propose that proper interaction between MLC1 internal repeats is of key relevance for proper protein folding and endoplasmic reticulum sorting. Similarly, recently reported MLC1 homo-trimeric complex in detergent micelles and proteoliposomes [ 24 ], suggests that mutations affecting MLC1 monomers interaction would also affect protein stability. However, the lack of a 3D structure at atomic resolution precludes the identification of putative protein-protein interaction regions.…”

Section: Novel Insights Into Glialcam/mlc1 Function By Alphafold Stru...mentioning

confidence: 80%

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GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts

Pla-Casillanis

Ferigle

Alonso-Gardón

et al. 2022

IJMS

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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects in MLC1 or glial cell adhesion molecule (GlialCAM) proteins. In addition, autoantibodies to GlialCAM are involved in the pathology of multiple sclerosis. MLC1 and GLIALCAM genes encode for membrane proteins of unknown function, which has been linked to the regulation of different ion channels and transporters, such as the chloride channel VRAC (volume regulated anion channel), ClC-2 (chloride channel 2), and connexin 43 or the Na+/K+-ATPase pump. However, the mechanisms by which MLC proteins regulate these ion channels and transporters, as well as the exact function of MLC proteins remain obscure. It has been suggested that MLC proteins might regulate signalling pathways, but the mechanisms involved are, at present, unknown. With the aim of answering these questions, we have recently described the brain GlialCAM interactome. Within the identified proteins, we could validate the interaction with several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptors GPR37L1 and GPR37. In this review, we summarize new aspects of the pathophysiology of MLC disease and key aspects of the interaction between GPR37 receptors and MLC proteins.

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Section: Novel Insights Into Glialcam/mlc1 Function By Alphafold Stru...mentioning

confidence: 58%

Section: Novel Insights Into Glialcam/mlc1 Function By Alphafold Stru...mentioning

confidence: 80%

GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts

Pla-Casillanis

Ferigle

Alonso-Gardón

et al. 2022

IJMS

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“…To investigate whether the low current density of the mBEST1 transfected cells was due to the low protein expression level, reduced membrane surface expression, or functional impairment of the mBEST1 channel, the surface biotinylated HEK293T cells expressing each BEST1 construct were subjected to the Western blot analysis to quantify the total expression levels and cell surface targeted fractions as previously described ( Fig. 2 ) ( 16 ). Apparently, we used BEST1 genes in-frame fused with C-terminal Flag tag to detect both hBEST1 and mBEST1 proteins simultaneously.…”

Section: Resultsmentioning

confidence: 99%

Cytosolic domain regulates the calcium sensitivity and surface expression of BEST1 channels in the HEK293 cells

Kim¹,

Hwang²,

Kim³

et al. 2023

BMB Rep

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BEST family is a class of Ca2+ -activated Cl-channels evolutionary well conserved from bacteria to human. The human BEST paralogs (BEST1-BEST4) share significant amino acid sequence homology in the N-terminal region, which forms the transmembrane helicases and contains the direct calcium-binding site, Ca 2+ -clasp. But the cytosolic C-terminal region is less conserved in the paralogs. Interestingly, this domain-specific sequence conservation is also found in the BEST1 orthologs. However, the functional role of the C-terminal region in the BEST channels is still poorly understood. Thus, we aimed to understand the functional role of the C-terminal region in the human and mouse BEST1 channels by using electrophysiological recordings. We found that the calcium-dependent activation of BEST1 channels can be modulated by the C-terminal region. The C-terminal deletion hBEST1 reduced the Ca 2+ dependent current activation and the hBEST1-mBEST1 chimera showed a significantly reduced calcium sensitivity to hBEST1 in the HEK293 cells. And the C-terminal domain could regulate cellular expression and plasma membrane targeting of BEST1 channels. Our results can provide a basis for understanding the C-terminal roles in the structure-function of BEST family proteins.

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“…Predictions and experimental studies show that the MLC1 protein has 8 transmembrane regions with both the amino- and the carboxy-terminus residing in the cytoplasm ( Figure 2B ). MLC1 most likely forms a trimeric structure in the membrane ( Hwang et al, 2021 ). The protein has very low homology with other proteins, with highest similarity (less than 20%) with the shaker-related voltage gated potassium channel Kv1.1 α-subunit ( Teijido et al, 2004 ; Brignone et al, 2015 ).…”

Section: Variantsmentioning

confidence: 99%

Megalencephalic leukoencephalopathy with subcortical cysts: a variant update and review of the literature

Passchier,

Bisseling,

Helman

et al. 2024

Front. Genet.

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The leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by infantile-onset macrocephaly and chronic edema of the brain white matter. With delayed onset, patients typically experience motor problems, epilepsy and slow cognitive decline. No treatment is available. Classic MLC is caused by bi-allelic recessive pathogenic variants in MLC1 or GLIALCAM (also called HEPACAM). Heterozygous dominant pathogenic variants in GLIALCAM lead to remitting MLC, where patients show a similar phenotype in early life, followed by normalization of white matter edema and no clinical regression. Rare patients with heterozygous dominant variants in GPRC5B and classic MLC were recently described. In addition, two siblings with bi-allelic recessive variants in AQP4 and remitting MLC have been identified. The last systematic overview of variants linked to MLC dates back to 2006. We provide an updated overview of published and novel variants. We report on genetic variants from 508 patients with MLC as confirmed by MRI diagnosis (258 from our database and 250 extracted from 64 published reports). We describe 151 unique MLC1 variants, 29 GLIALCAM variants, 2 GPRC5B variants and 1 AQP4 variant observed in these MLC patients. We include experiments confirming pathogenicity for some variants, discuss particularly notable variants, and provide an overview of recent scientific and clinical insight in the pathophysiology of MLC.

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Transmembrane topology and oligomeric nature of an astrocytic membrane protein, MLC1

Cited by 5 publications

References 65 publications

GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts

GPR37 Receptors and Megalencephalic Leukoencephalopathy with Subcortical Cysts

Cytosolic domain regulates the calcium sensitivity and surface expression of BEST1 channels in the HEK293 cells

Megalencephalic leukoencephalopathy with subcortical cysts: a variant update and review of the literature

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