MCOLN3 Membrane Protein Introduction

Introduction of MCOLN3

Mucolipin-3 (MCOLN3), also named TRPML3, belongs to the MCOLN (TRPML) subfamily of transient receptor potential (TRP) channels comprising three genes (MCOLN1-MCOLN3) in mammals. MCOLNs are the major Ca²⁺-permeable channels on late endosomes and lysosomes. They regulate the release of Ca²⁺ from organelles, which is important for various physiological processes, including organelle trafficking and fusion. MCOLN3 can be divided into three domains: the extra-cytosolic domain (ECD), the transmembrane channel domain (TMD), and the cytoplasmic domain. The ECD contains two β-sheets and two externally-helical helices, which form a cyclic tetramer that closes the outer-rotation side of the channel and is structurally similar to the ECD of MCOLN1 and PKD2. It has been shown by mutagenesis that the three histidines within the ECD play an important role in the pH sensing of MCOLN3. The location of these critical residues at the ECD-ECD and ECD-TMD interfaces suggests that pH sensing may involve in the histidine-mediated structural rearrangement.

Function of MCOLN3 Membrane Protein

It is documented that a dominant mutation in the MCOLN3 gene causes deafness and vestibular impairment characterized by HC loss, anatomical malformation of the stria vascularis and reduced endocochlear potential in the varitint-waddler (Va) mouse. MCOLN1 is expressed in all cell lysosomes, while MCOLN3 is only expressed in a small fraction of cells. This restricted expression suggests that cells expressing MCOLN3 may have specialized lysosomes. In fact, the neonatal intestinal cells expressing MCOLN3 have large lysosomes, which are specifically used for intracellular digestion of endocytic proteins from breast milk; melanocytes expressing mucolipin produce melanin from specialized pro-melanosome lysosomes. The marginal cells of the vascular streak also express MCOLN3, which uses the lysosome to localize the potassium KCNQ1 channel to their apical membrane.

Fig.1 Overall topology of the TRPML3 channel. (Hirschi, 2017)

Application of MCOLN3 Membrane Protein in Literature

1. 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 mucolipins 3 and 1 accelerate ARHL due to degeneration of auditory outer hair cells, which is the most common cause of human hearing loss and neurodegenerative diseases.

2. Hirschi M., et al. Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature. 2017, 550(7676):411-414. PubMed ID: 29019979
   
   

   This article suggests that the mucolipin domain is responsible for the binding of PtdIns(3,5)P2 and subsequent channel activation, and it acts as a "gated pulley" for lipid-dependent TRPML gating.

3. Zhou X., et al. Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nature Structural & Molecular Biology. 2017, 24(12):1146-1154. PubMed ID: 29106414
   
   

   This article suggests that by changing the S1 and S2 conformations, intraluminal pH and other physiological regulators such as PIP2 are novel mechanisms for regulating TRPML3.

4. Venkatachalam K., et al. The role of TRPMLs in endolysosomal trafficking and function. Cell Calcium. 2015, 58(1):48-56. PubMed ID: 25465891
   
   

   This article reviewed the functional and biophysical properties of cation channels, which represent the oldest and typical TRP channels.

5. Grimm C., et al. TRPML3. Springer Berlin Heidelberg. 2014, 659-674. PubMed ID: 24756725
   
   

   This article suggests that although the physiological roles of TRPML channels in the endolysosomal system are far from fully understood, they are presumed to be involved in the regulation of endolysosomal pH, fusion/fission processes, transport, autophagy and/or (hormone) secretion and exocytosis.

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Reference

1. Hirschi M, et al. (2017). Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature. 550(7676):411-414.

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