Abstract
In mammals and fungi, Nod-like receptors (NLR) activate downstream cell death execution proteins by a prion-like mechanism. In Podospora anserina, the NWD2 NLR activates the HET-S Helo-domain pore-forming protein by converting its prion-forming domain into a characteristic β-solenoid amyloid fold. The amyloid forming region of HET-S/s comprises two repetitions of a 21 amino acid motif. Herein, we systematically analyze the sequences of C-terminal regions of fungal HeLo and HeLo-like domain proteins to identify HET-s-related amyloid motifs (HRAM). We now identify four novel HRAM subfamilies in addition to the canonical HET-S/s subfamily. These novel motifs share the pseudo-repeat structure of HET-S/s and a specific pattern of distribution of hydrophobic and polar residues. Sequence co-variance analyses predict parallel in-register β-stacking of the two repeats and residue-residue interactions compatible with the β-solenoid fold. As described for HET-S, most genes encoding the HeLo proteins are adjacent to genes encoding NLRs also displaying HRAMs. The motifs of the NLRs are similar to those of their cognate HeLo-domain protein, indicating concerted evolution between repeats. This study shows that HET-s-related amyloid motifs are more common than anticipated and that they have diversified into discrete subfamilies that apparently share a common overall fold.
Highlights
In mammals and fungi, Nod-like receptors (NLR) activate downstream cell death execution proteins by a prion-like mechanism
The HET-s motif differs from these additional motifs by its pseudo-repeated structure, with two copies of the motif found on the effector protein and a single copy of the motif found in the NLR
As described for HET-S and NWD2, these proteins are encoded by genes that reside adjacent to genes encoding NLRs sharing the same motif
Summary
Nod-like receptors (NLR) activate downstream cell death execution proteins by a prion-like mechanism. We systematically analyze the sequences of C-terminal regions of fungal HeLo and HeLolike domain proteins to identify HET-s-related amyloid motifs (HRAM). In the fungus Podospora anserina, a prion amyloid motif is involved in the activation of the HET-S cell death inducing protein by a Nod-like receptor termed NWD210,11. Cell death is triggered when the PFD region of HET-S is converted to the β -solenoid fold This in turn induces refolding of the HET-S HeLo domain which exposes a N-terminal hydrophobic α -helix causing HET-S to behave as a pore-forming toxin[12]. Like the canonical HET-s-motif, these motifs are organized as imperfect repeat pairs in the C-terminal region of the HeLo domain proteins We collectively analyze these motifs and find that they correspond to four new subfamilies of HET-s-related motifs
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