MCOLN1 Membrane Protein Introduction

Introduction of MCOLN1

Mucolipin-1, also known as transient receptor potential mucolipin-1 (TRPML1), is a membrane protein consisting of 580 amino acids encoded by the MCOLN1 gene and has a molecular weight of approximately 65 kDa. Mucolipin-1 is predicted to have six transmembrane domains and is a member of the large family of transient receptor potential (TRP) cation channels. Mutations of the MCOLN1 gene result in the lysosomal storage disorder mucolipidosis type IV (MLIV). The efficient targeting of mucolipin-1 to lysosomes requires di-leucine motifs in both the N-terminal and the C-terminal cytosolic tails. Mucolipin-1 is widely expressed in mammalian cells of lysosome or endosomal membrane and is the main channel for lysosomal Ca²⁺ release, as well as a key regulator of lysosomal storage and transport. In addition, it is considered to be a regulator of amyloid-β autophagy and accumulation within neurons.

Function of MCOLN1 Membrane Protein

Mucolipins-1 is a non-selective, pH-regulated cation channel with a preference for monovalent cations, which might mediate the release of Ca²⁺ from the lysosomal or late endosomal lumen into the cytosol, thus regulating membrane trafficking, lysosomal biogenesis, and signal transduction. Mutations of MCOLN1 gene cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV), therefore, mucolipin-1 may have multiple functions in cells that are reflected by the general biochemical and clinical aspects of MLIV pathology. The constitutive achlorhydria in MLIV patients and the selective vacuolation in stomach parietal cells of MLIV patients suggests that mucolipin-1 is critical in HCI secretion. Moreover, the study of polycystin-2 in primary kidney cell cultures indicates that it is involved in lipid transport toward basolateral membranes. Finally, mucolipin-1 may also play a major role in the development of white matter tracts and in the maintenance of neurons and retinal cell integrity.

Fig.1 The structure of TRP protein. (Takahashi, 2012)

Application of MCOLN1 Membrane Protein in Literature

1. Sun X., et al. A negative feedback regulation of MTORC1 activity by the lysosomal Ca²⁺ channel MCOLN1 (mucolipin 1) using a CALM (calmodulin)-dependent mechanism. Autophagy. 2018, 14(1):38-52. PubMed ID: 29460684
   
   

   This article reports the cloning of a novel transient receptor potential cation channel gene and shows that this gene is mutated in patients with the disorder.

2. Zhang L., et al. Curcumin Exerts Effects on the Pathophysiology of Alzheimer’s Disease by Regulating PI(3,5)P2 and Transient Receptor Potential Mucolipin-1 Expression. Frontiers in Neurology. 2017, 8:531. PubMed ID: 29062301
   
   

   This article suggests that, to some extent, the effects of curcumin on the pathogenesis of AD are at least partially related to PI(3,5)P2 and TRPML1 expression levels.

3. Wiwatpanit T., et al. Codeficiency of Lysosomal Mucolipins 3 and 1 in Cochlear Hair Cells Diminishes Outer Hair Cell Longevity and Accelerates Age-Related Hearing Loss. Journal of Neuroscience. 2018, 38(13):3177-3189. PubMed ID: 29453205
   
   

   This article finds that mice lacking the lysosomal channels mucolipins 3 and mucolipins1 accelerate ARHL due to degeneration of auditory outer hair cells, and this is the most common cause of human hearing loss and neurodegenerative diseases.

4. Pravda L., et al. MOLEonline: a web-based tool for analyzing channels, tunnels and pores (2018 update). Nucleic Acids Research. 2018, 46(W1):W368-W373. PubMed ID: 29718451
   
   

   This article reveals the application of MOLE online for structural analyses of α-hemolysin and transient receptor potential mucolipin 1 (TRMP1) pores.

5. Wu G., et al. Identification of a single aspartate residue critical for both fast and slow calcium-dependent inactivation of the human TRPML1 channel. Journal of biological chemistry. 2018, 293(30):11736-11745. PubMed ID: 29884771
   
   

   This article identifies key residues critical for Ca²⁺-induced TRPML1 channel current inhibition and reveals pH-dependent regulation of this channel, providing important information for the detailed mechanism of action of human TRPM.

MCOLN1 Preparation Options

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Reference

1. Takahashi N, et al. (2012). TRP channels: sensors and transducers of gasotransmitter signals. Frontiers in Physiology. 3:324.

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