Chromosome-naïve global networks of initiators of hybrid assembly pathways of endogenous multiprotein complexes.

Molecular mechanisms governing initiation steps of the assembly of thousands of endogenous multi-protein complexes (EMCs) remain incompletely understood. Here, multiple lines of observations are reported reflecting the biological functions-aligned initiation sequence of hybrid assembly pathways (HAPs) of EMCs. HAPs postulate the creation of cell type-specific intracellular pools of hetero- and homodimers as the first step of chain reactions of protein-protein interactions (PPIs) of EMCs’ assemblies. The consensus action sequence of HAPs consists of: a) Initiation on genomic DNA templates of the formation of metastable hetero- and homodimers of EMCs’ protein constituents; b) Release of dimers from DNA templates for delivery to the EMCs assembly compartments; c) Assembly of defined EMCs by sequential on demand addition to preformed dimers serving as attractors of EMC-specific monomers’ ensembles. Chromosome-naïve scaffolds of PPIs contributing to creation of intracellular dimer pools constitute genome-wide networks of binding sites for 716 transcription factors (TFs), 534 of which manifest patterns of significantly enriched expression in 1358 brain regions. The initiators’ loci of HAPs appear to operate within nucleosome-depleted islands of transposable elements (TE) – derived sequences within transcriptionally silent heterochromatin. Performance of PPI DNA template-guided assembly lines of EMCs is illustrated in two concurrent modes of PPI cascades: TF-TF PPI chains and TF-PPI Hub protein chains. Regardless of the number of DNA-bound TFs initiating the multistep PPI sequences at PPI initiators (ranging from one to 716 TFs), both modes of operations reached the equilibrium at the PPI constituents saturation levels of ~245 proteins for TF-TF PPI and of ~351 proteins for TF-PPI Hub Proteins’ assembly chains. Regardless of TF panels bound at HAP initiators, proteins of PPI-guided ensembles are enriched in either defined sets of neuroanatomical structures (TF-TF PPI path) or among structural-functional constituents of synapses (PPI Hub proteins path). Examples of default operation modes of DNA-template-guided assemblies of hetero- and homodimers of Yamanaka factors, neurogenesis constituents, and principal protein components of postsynaptic density of excitatory and inhibitory synaptogenesis are reported. Altogether, this contribution reports the foundational evidence for further experimental and theoretical explorations of retrotransposon-seeded genome-wide codes for initiators of PPI chain reactions of protein dimerization creating pools of attractors to guide and accelerate the EMC assemblies.