TMEM132: an ancient architecture of cohesin and immunoglobulin domains define a new family of neural adhesion molecules

Abstract

Summary: The molecular functions of TMEM132 genes remain poorly understood and under-investigated despite their mutations associated with non-syndromic hearing loss, panic disorder and cancer. Here we show the full domain architecture of human TMEM132 family proteins solved using in-depth sequence and structural analysis. We reveal them to be five previously unappreciated cell adhesion molecules whose domain architecture has an early holozoan origin prior to the emergence of choanoflagellates and metazoa. The extra-cellular portions of TMEM132 proteins contain five conserved domains including three tandem immunoglobulin domains, and a cohesin domain homologue, the first such domain found in animals. These findings strongly predict a cellular adhesion function for TMEM132 family, connecting the extracellular medium with the intracellular actin cytoskeleton.

Contact: luis.sanchez-pulido@igmm.ed.ac.uk.

Supplementary information: Supplementary data are available at Bioinformatics online.

Fig. 1

Domain architecture and common features in the TMEM132 family. Schematic representation of conserved domains present in TMEM132 family members: a conserved region (CR; shown in red; see Supplementary Fig. S6) precedes a cohesin domain (blue; see Supplementary Fig. S5), and three adjacent BIG domains (orange; Supplementary Figs S3 and S4). The predicted intradomain and interdomain disulphide bridges of these BIG domains are indicated in the right panel (magenta and violet lines, respectively). The seven beta-strands, forming part of the immunoglobulin-like core of BIG domains, are labelled a-g following an established convention (Bork et al., 1994) (Supplementary Fig. S7). Evolutionarily conserved TMEM132 intracellular motifs putatively related with the control of actin cytoskeletal dynamics are: a putative serine phosphorylation motif (SP), a phosphatase-1 (PP1) interaction motif (RVxF) (Hendrickx et al., 2009; Heroes et al., 2013), and a WIRS (WAVE regulatory complex interacting receptor sequence) cytoplasmic motif (Chen et al., 2014)