What it is
By mining millions of AlphaFold2 models, the authors identified two human families of 'superdark' seven-transmembrane proteins (TM184 and PRRT) with structural homology to G-protein-coupled receptors (GPCRs), and showed they perform hallmark GPCR activities such as β-arrestin recruitment and GRK-dependent phosphorylation. Focusing on TM184C, the most broadly expressed and conserved of these, they found it localizes to dynamic intracellular vesicles that travel along microtubules and promote tunnelling-nanotube-like intercellular bridges mediating organelle sharing. TM184C also limits autophagic flux by restraining LC3B lipidation and autophagosome accumulation, a role conserved enough that the human protein restores autophagic body homeostasis in yeast lacking its homologue Hfl1.
Why it matters
Most protein annotation depends on sequence similarity, so proteins whose function lies beyond detectable homology stay dark. This work shows that structure-based mining can reach into that dark proteome, assigning a previously obscure protein family GPCR-like behavior and, for TM184C, concrete roles in autophagy, intercellular connectivity, and material exchange.
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Filed underAutophagy in Disease and Therapy, Cellular transport and secretion, Receptor Mechanisms and Signaling