Transmembrane protein 106B is a protein that is encoded by the TMEM106B gene. It is found primarily within neurons and oligodendrocytes in the central nervous system with its subcellular location being in lysosomal membranes. TMEM106B helps facilitate important functions for maintaining a healthy lysosome, and therefore certain mutations and polymorphisms can lead to issues with proper lysosomal function. Lysosomes are in charge of clearing out mis-folded proteins and other debris, and thus, play an important role in neurodegenerative diseases that are driven by the accumulation of various mis-folded proteins and aggregates. Due to its impact on lysosomal function, TMEM106B has been investigated and found to be associated to multiple neurodegenerative diseases.
Structure
Gene
In humans,TMEM106B is found on chromosome 7 at positions 12211270 - 12243367, totaling 32097 base pairs. The gene includes 9 exons and can give rise to 2 different isoforms, T185 and S185, which are formed by the risk and protective haplotypes, respectively.
Protein
TMEM106B is composed of 274 amino acids and it has a molecular weight of 31kDa. It is found in the membrane of a lysosome (transmembrane protein) and has its highest expression in the central nervous system, specifically within neurons and oligodendrocytes. The protein can be divided into 3 domains; N-terminal cytosolic domain, a transmembrane domain, and a C-terminal domain containing five N-glycosylation sites in the lumen. The exact mechanism of proteolytic processing for TMEM106B is not completely understood, but a protease cleaves the protein which releases the C-terminal domain into the lumen of the lysosome and creates a N-terminal fragment on the lysosomal membrane, which is further cleaved and processed by other proteases. The mechanisms behind the proteolysis of TMEM106B is of interest because it is thought to be a factor in what gives rise to TMEM106B fibril formation.
Fibrils
TMEM106B can form amyloid fibrils in a variety of neurodegenerative diseases and in neurologically healthy individuals, which have been structurally characterized by Cryo-EM. They can be made up of a single rod-like structure or a doublet of filaments forming a twisted ribbon, of which several polymorphisms have been identified; 4 singlets and 2 doublets. There has been no clear association between any of the polymorphisms to disease. The structure of the different polymorphisms is relatively conserved in the N-terminus, core, glycosylation sites (N145, N151, N164, and N183), and a disulfide bond between C214 an C253, the difference in structure is primarily within the C-terminal region.
Function
TMEM106B is a transmembrane lysosomal protein that is involved in several key functions for the lysosome. The lysosome is the organelle that clears out debris and unnecessary proteins.
Lysosomal size
Studies in cell lines have shown that over-expression of TMEM106B leads to larger lysosomes, which causes a negative-stress response within the cell and cell death. It is thought that lysosomal size may be partially dependent on pH and successful trafficking, as problems in either of these functions leads to clustering lysosomes and formation of large swollen vacuoles.
Lysosomal trafficking
Typically, lysosomes are trafficked along a microtubule by a motor protein and it has been observed that TMEM106B may play an important role in this process. In knock-out studies of TMEM106B inappropriate clustering of lysosomes is observed at the nucleus, and it has been shown this phenotype can be rescued by re-introducing TMEM106B into the system. In addition, it has been observed that knock-out of TMEM106B in mice leads to increased retrograde transport of lysosomes causing large lysosomal vacuoles to form at the distal end of neurons. TMEM106B has been shown to interact with microtubule associated protein 6 (MAP6), and it is thought that this interaction inhibits the retrograde transport of lysosomes, assisting with appropriate trafficking of lysosomes or inability to be transported along the microtubule by motor proteins.
Lysosomal pH
Lysosome are typically at an acidic pH of 4.5-5, maintaining this is very important to a lysosomes ability to perform degradation. Vacuolar ATPase (vATPase) maintains the acidic pH in lysosomes and it has been shown that TMEM106B interacts with accessory proteins of vATPase. When TMEM106B levels are increased a reduction in vATPase activity is observed and the lysosome is unable to maintain an acidic environment.