1.A.24.1.2
Connexin 32 (gap junction β1-protein), CX32 (transports adenosine better than CX43 does; Goldberg et al., 2002).  The carboxyl tail regulates gap junction assembly (Katoch et al. 2015).  The modeled channel pore-facing regions of TMSs 1 and 2 were highly sensitive to tryptophan substitution while lipid-facing regions of TMSs 3 and 4 were variably tolerant. Residues facing a putative intracellular water pocket (the IC pocket) were also sensitive.  Interactions important for voltage gating occurred mainly in the mid-region of the channel in TMS 1. TMS 1 of Cx43 was scanned revealing similar but not identical sensitivities (Brennan et al. 2015). Single point mutations in Cx32, which cause Charcot-Marie-Tooth disease, causes failure in membrane integration, transport defects and rapid degradation. Multiple chaperones detect and remedy this aberrant behavior including the ER-membrane complex (EMC) which helps insert low-hydrophobicity TMSs (Coelho et al. 2019). If they fail to integrate, they are recognized by the ER-lumenal chaperone BiP. Ultimately, the E3 ligase gp78 ubiquitinates Cx32, targeting it for degradation. Thus, cells use a coordinated system of chaperones for membrane protein biogenesis. Dileucine-like motifs in the C-terminal tail of connexin32 control its endocytosis and assembly into gap junctions (Ray et al. 2018).