PT  - JOURNAL ARTICLE
AU  - Pham, Chi L. L.
AU  - Strange, Merryn
AU  - O’ Carroll, Ailis
AU  - Shanmugam, Nirukshan
AU  - Sierecki, Emma
AU  - Gambin, Yann
AU  - Steain, Megan
AU  - Sunde, Margaret
TI  - The RHIM within the M45 protein from murine cytomegalovirus forms heteromeric amyloid fibrils with RIPK1 and RIPK3
AID  - 10.1101/324590
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 324590
4099  - http://biorxiv.org/content/early/2018/06/01/324590.short
4100  - http://biorxiv.org/content/early/2018/06/01/324590.full
AB  - The M45 protein from murine cytomegalovirus protects infected murine cells from death by necroptosis and can protect human cells from necroptosis induced by TNFR activation, when heterologously expressed. We show that the N-terminal 90 residues of the M45 protein, which contain a RIP Homotypic Interaction Motif (RHIM), are sufficient to confer protection against TNFR-induced necroptosis. This N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils and interacts with the RHIMs of human RIPK1 and RIPK3 kinases to form heteromeric amyloid fibrils in vitro. An intact RHIM core tetrad is required for the inhibition of cell death by M45 and we show that mutation of those key tetrad residues abolishes homo- and hetero-amyloid assembly by M45 in vitro, suggesting that the amyloidogenic nature of the M45 RHIM underlies its biological activity. Our results indicate that M45 mimics the interactions made by RIPK1 with RIPK3 in forming heteromeric amyloid structures.