Molecular architecture of TE-seeded chromosome-naive initiation networks of protein-protein interactions delineates the Human Protein Map of the assembly of multiprotein complexes

Abstract

Upon binding to transposable elements seeded DNA, initiator transcription factors are poised to activate the hybrid assembly pathways (HAP) of endogenous multiprotein complexes (EMC) by iteratively engaging protein-protein interaction (PPI) cascade and creating cell type-specific pools of protein dimers. Here, molecular features and inferred biological functions of PPI cascade constituents were elucidated within the context of cell type-specific intracellular protein monomer pools documented in the Human Protein Atlas (HPA) of 154 human cell types. The following key features of the molecular architecture and functional performance of the 4 families of PPI cascade constituents were documented within the HPA contexts of intracellular proteomes: a) the ubiquitous expression and balanced representation; c) the universal availability and engagements; d) constitutive {invariant) and cell type-specific assembly profiles of EMCs. The biological relevance of the PPI cascades is demonstrated by cell-type-resolved multiprotein complex-engagement analysis across the HPA of human body, which faithfully recovers without supervision the intrinsic lineage structures of EMCs and lineage-specific master-regulator multiprotein assemblies. PPI cascade constituents have the capacity to generate 51,830 protein dimers within the proteome availability contexts of 154 types of human cells. Present analyses revealed critical impacts of the persistence of proteinopathy proteins that may cause the damage to the PPI cascade performance by sequestering 44 synaptic proteins. The sequestration of synaptic proteins withdraws structural-functional components of synapses suggesting a mechanism contributing to the pathogenesis of neurodegeneration. Conversely, reconstitution of availability of defined synaptic structural proteins appears to restore stoichiometry and recovers the lost assembly of synaptic protein dimers.