The molecular chaperone paradigm has shaped modern views of assisted protein folding, yet it does not fully capture the physical context in which de novo folding occurs in cells. A defining feature of the cellular milieu is macromolecular tethering in cis, whereby nascent polypeptides remain physically linked—through covalent or persistent associations—to ribosomes, lipid bilayers, or pre-folded domains of multidomain proteins. Because molecular chaperones have traditionally been defined as reversible binders acting in trans, this cis-acting mode has remained conceptually underappreciated. Cellular macromolecules, by virtue of their steric bulk and surface charges, can suppress aggregation of tethered polypeptides, thereby increasing productive folding yield. By analogy to colloidal stability, this repulsion-mediated control of aggregation suggests that cellular macromolecules can exhibit intrinsic chaperone-like activity largely independent of whether the linkage occurs in cis or in trans. This property provides a conceptual basis for linking cis- and trans-acting chaperoning. Thus, macromolecular tethering in cis may constitute a built-in layer of cellular chaperoning, distinct in physical linkage yet mechanistically related to conventional molecular chaperones.
Choi et al. (Thu,) studied this question.