Rapid Coaggregation of Proteins Without Sequence Similarity:\nPossible Role of Conformational Complementarity

Despite\nextensive research on the sequence-determined self-assembly\nof both pathogenic and nonpathogenic proteins, the question of how\nthe sequence identity would influence the coassembly or cross-seeding\nof diverse proteins without distinct sequence similarity remains largely\nunanswered. Here, we demonstrate that the rapid coaggregation of proteins\nwith negligible sequence similarity is fundamentally governed by preferred\nheteromeric interactions between their partially unfolded states via\nthe gain of additional charge complementarity and hydrophobic interactions.\nThe partial loss of intramolecular interactions and concurrent gain\nof non-native intrinsically disordered regions with sticky groups\nbecome crucial for both aggressive heteromeric primary nucleation\nand secondary nucleation events. The results signify the direct relevance\nof sequence-independent conformational cross-talk between diverse\nproteins to the foundational events required for the growth of biological\nmultiprotein amyloid deposits.