Structure of the GOLD-domain seven-transmembrane helix protein family member TMEM87A

Abstract

TMEM87s are eukaryotic transmembrane proteins with two members (TMEM87A and TMEM87B) in humans. TMEM87s have proposed roles in protein transport to and from the Golgi, as mechanosensitive ion channels, and in developmental signaling. TMEM87 disruption has been implicated in cancers and developmental disorders. To better understand TMEM87 structure and function, we determined a cryo-EM structure of human TMEM87A in lipid nanodiscs. TMEM87A consists of a Golgi-dynamics (GOLD) domain atop a membrane spanning seven-transmembrane helix domain with a large cavity open to solution and the membrane outer leaflet. Structural and functional analyses suggest TMEM87A may not function as an ion channel or G-protein coupled receptor. We find TMEM87A shares its characteristic domain arrangement with seven other proteins in humans; three that had been identified as evolutionary related (TMEM87B, GPR107, and GPR108) and four previously unrecognized homologs (GPR180, TMEM145, TMEM181, and WLS)). Among these structurally related GOLD domain seven-transmembrane helix (GOST) proteins, WLS is best characterized as a membrane trafficking and secretion chaperone for lipidated Wnt signaling proteins. We find key structural determinants for WLS function are conserved in TMEM87A. We propose TMEM87A and structurally homologous GOST proteins could serve a common role in trafficking membrane-associated cargo.

Structural insights into ion conduction by novel cation channel, TMEM87A, in Golgi apparatus

“…Human TMEM87A (hTMEM87A) and its homolog hTMEM87B, members of the Lung Seven Transmembrane Receptor (LUSTR) family 1 , are mainly present within Golgi. hTMEM87A is proposed to have a role in endosome-to-Trans Golgi Network (TGN) retrograde transport 2,5 which is also supported by its structural similarity with the Wnt transporter protein, Wntless 15 . However, a fraction of hTMEM87A localizes to the plasma membrane in cancer cells such as melanoma and glioblastoma multiforme (GBM), where it is associated with mechanosensitive cation channel activity 4,16 .…”

“…In this work, we determined the high-resolution cryo-EM structures of hTMEM87A in complex with the Golgi membrane phospholipid PE and the pharmacological inhibitor gluconate. Because the domain arrangement of hTMEM87A closely resembles that of Wntless, a regulator of Wnt protein sorting and secretion, and other GOLD domain seven-transmembrane helix (GOST) proteins 15 , the most parsimonious conclusion is that hTMEM87A is involved in the trafficking, secretion, and sorting of yet unidentified proteins. While future studies will be required to examine its function, our structure analysis of hTMEM87A, complemented by MD simulations and electrophysiological analysis, provide crucial insights into mechanistic aspects of hTMEM87A as a non-selective voltage-gated cation channel.…”

GolpHCat (TMEM87A): a unique voltage-gated and pH-sensitive cation channel in the Golgi

“…However, it has not been determined whether TMEM87A is an ion channel or not. Indeed, TMEM87A has been recently proposed as either a pore-forming or auxiliary subunit for a mechanosensitive ion channel 24 , which has been immediately contradicted by the lack of mechanosensitive channel activities in TMEM87A reconstituted proteoliposome 25 .…”

To be or not to be an ion channel: cryo-EM structures have a say

“…It was thus renamed Elkin1, from the Greek word Elko ("to pull"). The cryo-EM structure of human TMEM87A published recently (Hoel et al , 2022) shows that TMEM87A is a monomer with a sandwich-like extracellular domain and a transmembrane domain of 7 TMs (Fig. S10).…”

“…S10). Ion-conducting pore cannot be identified from the structure, and the authors also failed to record mechanosensitive currents from TMEM87A reconstituted proteoliposomes (Hoel et al , 2022). Further structural analyses revealed that TMEM87A is neither a G protein-coupled receptor, but shares similarity with several Golgi-dynamics (GOLD) domain seven-transmembrane helix (GOST) proteins that function in membrane-associated protein trafficking.…”