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

  1. Christopher M Hoel
  2. Lin Zhang
  3. Stephen G Brohawn

  • Curated by eLife

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    eLife assessment

    This work addresses the mechanisms of action of the transmembrane proteins TMEM87A and TMEM87B, which are thought to play a role in protein transport, but have been implicated in other processes as well, such as signaling and acting as mechanosensitive ion channels. The study represents an important advance of the understanding of this poorly characterized family of proteins. While the structure is of low resolution, it is well interpreted, and authors take good advantage of AlphaFold2 to gain insights into potential function. The work is of interest to colleagues studying transporters and ion channels.

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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 GO LD domain s even- t ransmembrane 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.

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  1. Version published to 10.7554/elife.81704 on eLife
  2. eLife

    eLife assessment

    This work addresses the mechanisms of action of the transmembrane proteins TMEM87A and TMEM87B, which are thought to play a role in protein transport, but have been implicated in other processes as well, such as signaling and acting as mechanosensitive ion channels. The study represents an important advance of the understanding of this poorly characterized family of proteins. While the structure is of low resolution, it is well interpreted, and authors take good advantage of AlphaFold2 to gain insights into potential function. The work is of interest to colleagues studying transporters and ion channels.

  3. eLife

    Reviewer #1 (Public Review):

    This work addresses the mechanisms of transmembrane proteins TMEM87A and TMEM87B, which are thought to play a role in protein transport, but have been implicated in other processes as well, such as signaling and acting as mechanosensitive ion channels.

    The authors have determined a cryo-EM structure of human TMEM87A, finding that the protein consists of a Golgi-dynamics (GOLD) domain, sitting on top of a membrane spanning seven-transmembrane helical domains. The GOLD domain possesses a large cavity which is open to solution and the membrane. A related structure has been found for a protein Wntless known to promote membrane transport and secretion of the Wnt signaling proteins, and are lipid-modified.

    Based on this similarity, the authors propose TMEM87A and other GOLD domain proteins are involved in transport of other membrane-associated proteins, such as ghrelin and several cytokines. This is in contrast to the proposed roles of TMEM87 as a signaling or ion channel molecule. The authors report on no evidence of channel activity in reconstituted liposomes carrying the TMEM 87 protein. However, no target molecule has been identified.

    The work is based on a combination of Cryo-EM experiments and use of Alpha-fold-based prediction. It is competently done and the results are of interest to structural biologists. However, in the absence of a known target molecule of TMEM87A, a protein whose transport depends on TMEM87A, the results are of limited interest to a wider audience.

  4. eLife

    Reviewer #2 (Public Review):

    In this report, Hoel and colleagues present evidence that the TMEM87 proteins are members of a larger family of GOLD domain seven-transmembrane helix proteins that consist of a 7 transmembrane helix containing membrane domain and an extracellular / luminal Golgi-dynamics (GOLD) domain. Combining AlphaFold2 modelling with a low-resolution (~4.7) cryo-EM map, the authors were able to build a model of human TMEM87A. Comparisons revealed that TMEM87A is most structurally related to Wntless, including a large membrane accessible cavity on the extracellular / luminal side of the 7 TM domain. A non-protein density was resolved in this cavity in TMEM87A that may correspond to a lipid molecule.

    This study represents an important advance of the understanding of this poorly characterized family of proteins. While the structure is of low resolution, it is well interpreted, and authors take good advantage of AlphaFold2 to gain insights into potential function.

  5. eLife

    Reviewer #3 (Public Review):

    In this well-written manuscript, Hoel et al., determine the 4.7 Å cryo-EM structure of TMEM87A - a protein of unknown function but proposed to have roles in protein transport to and from the Golgi, mechanosensitive ion channels, and in developmental signaling. The team perform an electrophysiological assay to demonstrate that under their experimental conditions the protein is not a mechanosensitive channel, and compare their structures to other structures and Alphafold models to place this protein in a newly defined protein family which they suggest may have roles in trafficking membrane-associated cargo.

    Given that the only data provided in this manuscript (aside from a single electrophysiological assay) is a low resolution cryo-EM map this manuscript has really on reached the hypothesis generating stage. No experiments to demonstrate what the role of this protein is have been performed.

  6. eLife

    Reviewer #4 (Public Review):

    This study revealed the structure of TMEM87A for the first time. Unexpectedly, the authors found that TMEM87A shared high structural similarity with WLS that mediates Wnt secretion and trafficking. Particularly, these two proteins share a similar extracellular GOLD domain and a large cavity that is accessible from both the extracellular side and the membrane. Through structural comparison, the authors have also identified a few other membrane proteins that share similar architecture with TMEM87A/WLS. These findings define a new membrane protein family that may play important roles in membrane-associated protein trafficking.

    The authors also provided structural analyses and functional characterizations that suggest TMEM87A might function differently from GPCRs or ion channels. This proposal is reasonable. More experimental evidence is needed in either this study or future studies.

    Overall, the findings from this study are highly interesting. This work provides a molecular framework for future elucidation of TMEM87A's functional roles and provides important and novel insights into this newly defined family of membrane proteins, and more broadly protein trafficking process.

  7. Version published to 10.1101/2022.06.20.496907v1 on bioRxiv