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

Tim P Levine

doi:10.1002/prot.26201

Abstract

TMEM106B is an integral membrane protein of late endosomes and lysosomes involved in neuronal function, its overexpression being associated with familial frontotemporal lobar degeneration, and point mutation linked to hypomyelination. It has also been identified in multiple screens for host proteins required for productive SARS-CoV-2 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 nonstandard way to show that the lumenal portion of TMEM106B is a member of the late embryogenesis abundant-2 (LEA-2) domain superfamily. More sensitive tools (HMMER, HHpred, and trRosetta) extended this to predict LEA-2 domains in two yeast proteins. One is Vac7, a regulator of PI(3,5)P2 production in the degradative vacuole, equivalent to the lysosome, which has a LEA-2 domain in its lumenal domain. The other is Tag1, another vacuolar protein, which signals to terminate autophagy and has three LEA-2 domains in its lumenal domain. Further analysis of 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.

Highlights

Proteins of unknown function persist as a sizable minority in all organisms, with 15% of yeast and human proteins still having no informative description of their function at the molecular level.[1]
Together with its predicted short unstructured N-terminal cytoplasmic domain and single transmembrane helix (TMH), these results indicate that Tag[1] is a second late embryogenesis abundant-2 (LEA-2) protein in budding yeast (Figure 2F)
The link between TMEM106B and LEA-2 is so solid that it can be made with PSI-BLAST

Summary

| INTRODUCTION

Proteins of unknown function persist as a sizable minority in all organisms, with 15% of yeast and human proteins still having no informative description of their function at the molecular level.[1]. The TMEM106B protein has been localized to late endosomes and lysosomes,[3,12,16,17] and it has been shown to be. A major factor that might have contributed to TMEM106B remaining among the proteins of unknown function at the molecular level is that no homologues are available for comparative cell biological study in genetically tractable model organisms, including Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, and Schizosaccharomyces pombe.[22] To address this, I examined the sequence of TMEM106B using bioinformatics tools. Examination of the structure of an archaeal LEA-2 domain showed that it is a lipid transfer protein, which suggests specific modes of action for TMEM106B, Vac[7], and Tag[1], along with all LEA-2 proteins, related to sensing and/or transferring lipids

| METHODS

| RESULTS

Findings

| DISCUSSION