NatureSep 10, 2026

TM184C is a receptor-like protein that controls cell communication and self-cleaning processes

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 11, 2026

Abstract

Two human families of superdark seven-transmembrane proteins have been identified with structural similarities to G-protein-coupled receptors.

Superdark proteins TM184 and PRRT share structural features with G-protein-coupled receptors (GPCRs).
TM184C, the most widely expressed superdark protein, is located in dynamic intracellular vesicles instead of the plasma membrane.
These vesicles facilitate intercellular connections, promoting organelle sharing and movement along microtubules.
The function of TM184C requires its C-terminal tail and specific motifs associated with GPCR activity.
TM184C also limits the accumulation of autophagic bodies, a function conserved across species, as it restores autophagy in yeast lacking its homologue.

Simplified

Sequence similarity underlies most protein annotation, yet many functions remain hidden beyond detectable homology^1-3. By mining millions of AlphaFold2 models^4,5, we identify two human families of 'superdark' seven-transmembrane proteins-TM184 and PRRT-with structural homology to G-protein-coupled receptors (GPCRs). These proteins exhibit hallmark GPCR activities, including β-arrestin recruitment and GPCR kinase (GRK)-dependent phosphorylation. Here we focus on TM184C-the most broadly expressed and evolutionarily conserved superdark GPCR-like protein, which localizes to highly dynamic intracellular vesicles rather than the plasma membrane. These vesicles move along microtubules, accumulate in cell projections and promote the formation of tunnelling nanotube- and tumour microtubule-like intercellular connections. These bridges mediate organelle sharing through a process that requires the TM184C C-terminal tail and its arrestin code motif⁶, linking GPCR-like β-arrestin and GRK regulation to vesicle function and intercellular connectivity. TM184C also constrains autophagic flux by limiting LC3B lipidation and autophagosome accumulation-a role that is deeply conserved, as human TM184C restores autophagic body homeostasis in yeast lacking its homologue, Hfl1. Together, these findings illustrate how structure-based protein discovery can illuminate the dark proteome and identify TM184C as an ancient GPCR-like regulator of autophagy, intercellular connectivity and material exchange.

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TM184C is a receptor-like protein that controls cell communication and self-cleaning processes

Abstract

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