The structure of ligand binding sites has profound consequences for the evolution of function of protein complexes, particularly in homomers. Homomers with multichain binding sites (MBS) are characterized with more conserved binding sites and quaternary structure, and qualitatively different allosteric pathways than homomers with singlechain binding sites (SBS) or monomers. Here we show that 1) MBS homomers have significantly more long-range residue-residue interactions than SBS homomers or monomers, indicating that they have more complex folds and are more prone for misfolding; 2) In humans the interactome of MBS homomers is enriched in proteins that aid folding and assembly, including chaperones and chaperonins; 3) The sequences and structures of MBS and SBS homomers show qualitatively different distributions of frustrated residues, aggregation prone regions and interface residues, indicating that their interactions with the proteostasis network are different, and suggesting that SBS homomers are folded and assembled cotranslationally, while MBS homomers are not, and rely on more advanced folding-assistance and quality control mechanisms by chaperones and chaperonins.