Invisible but not inaccessible-Revealing transient oligomers formed by intrinsically disordered proteins with solution NMR and complementary methods.

Abstract

Intrinsically disordered proteins (IDPs) are often readily characterized as soluble monomers, whereas their biological and pathological roles frequently involve transient, heterogeneous, or sparsely populated oligomers. Such assemblies are often described as 'invisible' but invisibility is method-dependent: Oligomers that escape direct detection by one technique may remain accessible through indirect or complementary measurements. Solution NMR is uniquely positioned to exploit exchange between observable monomers and NMR-invisible oligomers, providing residue-specific information on populations, kinetics, and intermolecular contacts. Other methods report on mass, stoichiometry, dimensions, morphology, or site-specific distance distributions. Here, we discuss how integrating orthogonal measurements can overcome method-specific blind spots and yield a self-consistent model that simultaneously accounts for structure, populations, exchange kinetics, and morphology, something no single method can provide.