1.A.78 The K+-selective Channel in Endosomes and Lysosomes (KEL) Family
Organelle K+ conductance studies revealed a major K(+)-selective channel, KEL or TMEM175, on endosomes and lysosomes (Cang et al. 2015). Unlike any of the approximately 80 plasma membrane K+ channels in mammals, TMEM175 has two repeats of 6 TMSs and has no GYG K+ channel sequence signature in a pore (P) loop. Lysosomes lacking TMEM175 exhibit no K+ conductance, have a markedly depolarized Δpsi and little sensitivity to changes in [K+]. These mutants have compromised luminal pH stability and abnormal fusion with autophagosomes during autophagy. Thus, TMEM175 comprises a K+ channel that underlies the molecular mechanism of lysosomal K+ permeability (Cang et al. 2015).
The generalized reaction catalyzed by KEL is:
K+(in the lumen of endosomes and lysosomes) ⇌ K+ (cytoplasm)
Endosomal/Lysosomal K+ channel of 504 aas and 12 TMSs with two 6 TMS repeat units, KEL or TMEM175 (Cang et al. 2015). A mutation in the encoding gene was associated with Parkinson's disease (Jing et al. 2015). TMEM175 plays a direct and critical role in lysosomal and mitochondrial function as well as Parkinson's Disease (PD) pathogenesis (Jinn et al. 2017).
KEL or TMEM175 of Homo sapiens
TMEM175 of 506 aas and 12 TMSs
TMEM175 of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes)
TMEM175 of 598 aas and 12 TMSs.
TMEM175 of Salpingoeca rosetta
DUF211/TMEM175 of 206 aas and 6 TMSs.
TMEM175 of Fibrella aestuarina
TMEM175 lysosomal K+ channel of 203 aas and 6 TMSs. It's 3-d structure reveals a novel tetrameric arrangement (Lee et al. 2017). All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity (Lee et al. 2017).
TMEM175 of Chamaesiphon minutus
PF06736/TMEM175 of 198 aas and 6 TMSs.
TMEM175 of Leptospira inadai
TMEM175 of 206 aas and 5 TMSs
TMEM175 of Streptomyces collinus
Uncharacterized protein of 216 aas and 6 TMSs
UP of Deinococcus radiodurans
DUF1211/TMEM175 of 235 aas and 5 or 6 TMSs
TMEM175 of Azospirillum brasilense
DUF1211 family member of 205 aas and 5 TMSs
DUF1211 protein of Methanobacterium lacus
Uncharacterized protein of 210 aas and 6 TMSs
UP of Methanospirillum hungatei
Uncharacterized protein of 195 aas and 6 TMSs.
UP of Catellicoccus marimammalium
TMEM175 homologue of 197 aas and 5 or 6 TMSs. It is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability of lysosomes. It contains two homologous copies of a 6 TMS domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels (Lee et al. 2017). The architecture represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TMS1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TMS1 form a bottleneck along the ion conduction pathway and serve as the selectivity filter. Mutagenesis analyses suggested that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family (Lee et al. 2017).
TMEM175 homologue of Chamaesiphon minutus