TMEM106B, a risk factor for FTLD and aging, has an intrinsically disordered cytoplasmic domain.

Jian Kang,Jianxing Song,Liangzhong Lim,Patrick Van Der Wel

doi:10.1371/journal.pone.0205856

Jian Kang, Jianxing Song + Show 2 more

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https://doi.org/10.1371/journal.pone.0205856

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Journal: PloS one	Publication Date: Oct 17, 2018
Citations: 7	License type: CC BY 4.0

Affiliation: National University of Singapore

Abstract

TMEM106B was initially identified as a risk factor for FTLD, but recent studies highlighted its general role in neurodegenerative diseases. Very recently TMEM106B has also been characterized to regulate aging phenotypes. TMEM106B is a 274-residue lysosomal protein whose cytoplasmic domain functions in the endosomal/autophagy pathway by dynamically and transiently interacting with diverse categories of proteins but the underlying structural basis remains completely unknown. Here we conducted bioinformatics analysis and biophysical characterization by CD and NMR spectroscopy, and obtained results reveal that the TMEM106B cytoplasmic domain is intrinsically disordered with no well-defined three-dimensional structure. Nevertheless, detailed analysis of various multi-dimensional NMR spectra allowed defining residue-specific conformations and dynamics. Overall, the TMEM106B cytoplasmic domain is lacking of any tight tertiary packing and relatively flexible. However, several segments are populated with dynamic/nascent secondary structures and have relatively restricted backbone motions on ps-ns time scale, as indicated by their positive {1H}-15N steady-state NOE. Our study thus decodes that being intrinsically disordered may allow the TMEM106B cytoplasmic domain to dynamically and transiently interact with a variety of distinct partners.

Highlights

Transmembrane protein 106B (TMEM106B) is 274-residue protein whose gene locus was initially identified by a genome-wide association study to be a risk factor for the occurrence of frontotemporal lobar degeneration (FTLD), which is the second most common form of progressive dementia in people under 65 years [1,2]
To facilitate experimental investigations, the cytoplasmic domain of TMEM106B was first assessed by a variety of bioinformatics tools to gain insights into its amino acid composition, ordered/disordered regions and secondary structure
The disorder scores of most residues predicted by IUPred are > 0.5 (Fig 1D), implying that it might be intrinsically disordered as we previously observed on Nogo domains [16,26]

Summary

Introduction

Transmembrane protein 106B (TMEM106B) is 274-residue protein whose gene locus was initially identified by a genome-wide association study to be a risk factor for the occurrence of frontotemporal lobar degeneration (FTLD), which is the second most common form of progressive dementia in people under 65 years [1,2]. In 2012 it was reported that TMEM106B SNPs might be critical for the pathological presentation of Alzheimer disease [3]. The risk allele of TMEM106B was found to accompany significantly reduced volume of the superior temporal gyrus, most markedly in the left hemisphere [4], which includes structures critical for language processing, usually affected in FTLD patients [5]. TMEM106B was reported to be a genetic modifier of disease in the carriers of C9ORF72 expansions [6].

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