Evolutionary link between metazoan RHIM motif and prion-forming domain of fungal heterokaryon incompatibility factor HET-s/HET-s

Abstract

The Rip homotypic interaction motif (RHIM) is a short, non-globular sequence stretch that mediates a key interaction of mammalian necroptosis signaling. In order to understand its unusual oligomerization properties, we set out to trace the evolutionary origins of the RHIM motif by identifying distantly related protein motifs that might employ the same binding mode. The RHIM motif was found to be related to the prion-forming domain of the HET-s protein, which oligomerizes by forming structurally well-characterized fibrils and is involved in fungal heterokaryon incompatibility. This evolutionary relationship explains the recently reported propensity of mammalian RHIM motifs to form amyloid fibrils, but suggests that these fibrils have a different structural architecture than currently assumed. These findings, together with numerous observations of RHIM-like motifs in immunity proteins from a wide range of species, provide insight to the modern innate immunity pathways in animals, plants and fungi.

As a toxin dies a prion comes to life: A tentative natural history of the [Het-s] prion

“…25 Interestingly, the RHIM amyloid motif which scaffolds necrosome formation appears evolutionary related to the HET-s motif. 26 While some aspects of NWD2 amyloid signaling have been explored, a large number of mechanistic questions now emerge. Does HET-S detach from the NWD2 amyloid hub after conversion?…”

On the evolutionary trajectories of signal-transducing amyloids in fungi and beyond

“…While there is no precise structural information regarding the amyloid form of the RHIM motif, a recent study suggest that it might form a HET-S/s-like amyloid fold and that an evolutionary relation, based on sequence alignments and HMMs (Hidden Markov Model) comparisons, exists between the 2 amyloid domains. 25 The RHIM motif aligns with the R1/R2 repeats of the PFD and seems to be of approximately the same size. Five hydrophobic positions that constitute the core of the HET-S/s b-solenoid fold, are conserved across the RHIM motif sequences, as is a position with a functionally important glycine residue for both motifs.…”

“…Five hydrophobic positions that constitute the core of the HET-S/s b-solenoid fold, are conserved across the RHIM motif sequences, as is a position with a functionally important glycine residue for both motifs. 13,25 The RHIM motif, unlike the 2 repeats of the HET-S/ s PFD, is found in only one copy on RIP1 and RIP3 kinases. In this regard, it is more similar to the R0 motif, found in only one copy on the NWD2 NLR-like receptor in P. anserina.…”

“…Yet, another human protein ZBP1 (Z-DNA binding protein) -an innate immunity sensor for foreign DNA -is shown to have 2 or 3 successive RHIM motifs. 25 Furthermore, proteins from Branchiostoma, have also been reported to bear 2 repeats of the RHIM motif, disposed next to domains otherwise involved in metazoan innate immunity. 25 The evolutionary constraints defining the number of amyloidogenic repetitions found in different proteins are not well understood today.…”

“…25 Furthermore, proteins from Branchiostoma, have also been reported to bear 2 repeats of the RHIM motif, disposed next to domains otherwise involved in metazoan innate immunity. 25 The evolutionary constraints defining the number of amyloidogenic repetitions found in different proteins are not well understood today. It is possible that the nature of the motif itself, the spacing between the repetitions of the motif (if it exists in repeated form), and/or the mode of nucleation, may all influence to some extent the copy number distribution of the amyloidogenic motifs.…”