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Research Themes Protein design

Protein Folding and Misfolding: Beneficial Aggregation

SBKB [doi:10.1038/sbkb.2015.2]
Featured Article - March 2015
Short description: The ERAD-associated lectin Yos9 forms aggregates in the presence of misfolded substrates.

Quantification of the binding of Yos9(22–421) to each amino acid of CYP*, determined by averaging the intensities of peptide spots containing a given amino acid. Figure from ref. 1 , © 2014 The American Society for Biochemistry and Molecular Biology

En route to their final destination, nascent proteins of the secretory pathway are trafficked through the endoplasmic reticulum (ER), where they fold into native conformations. When folding goes awry, one pathway that disposes of misfolded proteins is ER-associated degradation (ERAD). Weissman and colleagues (PSI HOMEO) now shed light on ERAD regulation through the analysis of Yos9—an ER-resident lectin that mediates the clearance of glycoproteins.

Two signals within misfolded glycoproteins ensure substrate specificity during ERAD: the exposure of glycans with a terminal α1,6-linked mannose, and poorly characterized unfolded-protein determinants. The role of Yos9 in recognition of the glycan component is well established, and there is evidence that it might also interact with the protein signals.

The authors investigated whether Yos9 integrates those two signals. They used Yos9(22–421), a truncated variant of Yos9 that forms a compact stable domain capable of mediating degradation of the model ERAD substrate CYP* with the same efficiency as the full-length Yos9. In vitro, Yos9(22–421) could bind to four specific non-glycosylated segments of CYP*, three of which happened to be near glycan groups. This observation not only alludes to substrate specificity of Yos9, but also hints that the proximity of the peptide segments and the glycans that are recognized by Yos9 might allow crosstalk between these two signals.

As the CYP* peptides identified are unlikely to be soluble, the authors switched to two other model misfolded proteins for studies in solutions: the hydrophobic peptide ΔEspP and the unfolded protein Δ131Δ. In both cases, Yos9 bound to the substrates non-specifically, which suggests that the misfolded substrates' overall characteristics, such as hydrophobicity, determine recognition by Yos9. What's more, in the presence of ΔEspP and Δ131Δ—but not of a control protein—Yos9 formed aggregates, which were not affected by changes in solution conditions such as pH alterations. Mutations in either the dimer interface of Yos9 or its hydrophobic groove did not affect aggregate formation.

Oligomerization-mediated regulation has precedence in clearance of misfolded proteins, as part of the unfolded protein response pathway. But what could be the biological significance of Yos9 aggregation? The team speculates that aggregation might facilitate information transfer from Yos9 to Hrd1—an ERAD factor also known to form oligomers.

Sadaf Shadan

References

  1. M.H. Smith, E.H. Rodriguez & J.S. Weissman Misfolded proteins induce aggregation of the lectin Yos9.
    J Biol Chem. 289, 25670-7 (2014). doi:10.1074/jbc.M114.583344

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