8.A.145.  The TMEM147 (TMEM147) Family

McGilvray et al. 2020 described a ~ 360 kDa ribosome-associated complex comprising the core Sec61 channel (TC# 3.A.5.9.1) and five accessory factors: TMCO1 (TC# 1.A.106.1.1), CCDC47 (TC# 8.A.142.1.1) and the Nicalin (TC# 8.A.144.1.1)-TMEM147 (TC# 8.A.145.1.1)-NOMO 2 (TC# 8.A.146.1.1) complex. Cryo-EM revealed a large assembly at the ribosome exit tunnel organized around a central membrane cavity. Similar to protein-conducting channels that facilitate movement of TMSs, cytosolic and luminal funnels in TMCO1 and TMEM147, respectively, suggested routes into the central membrane cavity. High-throughput mRNA sequencing showed selective translocon engagement with hundreds of different multi-pass membrane proteins. Consistent with a role in multi-pass membrane protein biogenesis, cells lacking different accessory components of this complex showed reduced levels of one such client, the glutamate transporter EAAT1 (TC# 2.A.23.2.6). These findings identified a human translocon complex and provided a molecular framework for understanding its role in multi-pass membrane protein biogenesis (McGilvray et al. 2020).

The nuclear envelope (NE) and the endoplasmic reticulum (ER) collaborate to control a multitude of nuclear and cytoplasmic actions. TMEM147 localizes to both NE and ER, and through direct and indirect interactions regulates processes as varied as production and transport of multipass membrane proteins, neuronal signaling, nuclear-shape, lamina and chromatin dynamics and cholesterol synthesis. Aiming to delineate the emerging multifunctionality of TMEM147, Maimaris et al. 2021 set first, to assess potentially more fundamental effects of TMEM147 on the ER and, second, to identify significantly TMEM147-associated cell-wide protein networks and pathways. Quantifying curved and flat ER markers RTN4 and CLIMP63/CKAP4, respectively, they found that TMEM147 silencing causes area and intensity increases for both RTN4 and CLIMP63, and the ER in general, with a profound shift toward flat areas, concurrent with reduction in DNA condensation. Protein network and pathway analyses based on comprehensive compilation of TMEM147 interactors, targets and co-factors served to manifest novel and established roles for TMEM147. Thus, algorithmically simplified significant pathways reflect TMEM147 function in ribosome binding, oxidoreductase activity, G protein-coupled receptor activity and transmembrane transport, while analysis of protein factors and networks identified hub proteins and corresponding pathways as potential targets of TMEM147 action (Maimaris et al. 2021).

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