TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins

Abstract

TMEM106B is an integral membrane protein of late endosomes and lysosomes involved in neuronal function, its over-expression being associated with familial frontotemporal lobar degeneration, and under-expression linked to hypomyelination. It has also been identified in multiple screens for host proteins required for productive SARS-CoV2 infection. Because standard approaches to understand TMEM106B at the sequence level find no homology to other proteins, it has remained a protein of unknown function. Here, the standard tool PSI-BLAST was used in a non-standard way to show that the lumenal portion of TMEM106B is a member of the LEA 2 domain superfamily. The non-standard tools (HMMER, HHpred and trRosetta) extended this to predict two yeast LEA 2 proteins in the lumenal domains of the degradative vacuole, equivalent to the lysosome: one in Vac7, a regulator of PI(3,5)P2 production, and three in Tag1 which signals to terminate autophagy. Further analysis of previously unreported LEA 2 structures indicated that LEA 2 domains have a long, conserved lipid binding groove. This implies that TMEM106B, Vac7 and Tag1 may all be lipid transfer proteins in the lumen of late endocytic organelles.

Roles of PIKfyve in multiple cellular pathways

“…Deletion of Vac7 in yeast results in nearly undetectable levels of PI(3,5)P 2 and an enlarged vacuole [ 22 ]. TMEM106B has been proposed as a mammalian homolog for Vac7 based on bioinformatics methods [ 23 ]. It is currently unknown whether this protein regulates the PIKfyve complex in mammals.…”

The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus

“…Given that (i) many of the most important gene variants affecting dementia risk regulate lipid transport and catabolism [53], (ii) structural modelling has proposed a lipid binding function for TMEM106B [54], and (iii) TMEM106B protein levels were correlated with proteins regulating fatty acid and lipid metabolism, we used lipidomic analysis to determine how dementia risk allele rs1990622-A affects lipid composition in the hippocampus of cognitively normal humans. A total of 234 phospholipids, sphingolipids, and neutral lipids were quanti ed by LC-MS/MS.…”