Unified understanding of folding and binding mechanisms of globular and intrinsically disordered proteins

Abstract

Extensive experimental and theoretical studies have advanced our understanding of the mechanisms of folding and binding of globular proteins, and coupled folding and binding of intrinsically disordered proteins (IDPs). The forces responsible for conformational changes and binding are common in both proteins; however, these mechanisms have been separately discussed. Here, we attempt to integrate the mechanisms of coupled folding and binding of IDPs, folding of small and multi-subdomain proteins, folding of multimeric proteins, and ligand binding of globular proteins in terms of conformational selection and induced-fit mechanisms as well as the nucleation–condensation mechanism that is intermediate between them. Accumulating evidence has shown that both the rate of conformational change and apparent rate of binding between interacting elements can determine reaction mechanisms. Coupled folding and binding of IDPs occurs mainly by induced-fit because of the slow folding in the free form, while ligand binding of globular proteins occurs mainly by conformational selection because of rapid conformational change. Protein folding can be regarded as the binding of intramolecular segments accompanied by secondary structure formation. Multi-subdomain proteins fold mainly by the induced-fit (hydrophobic collapse) mechanism, as the connection of interacting segments enhances the binding (compaction) rate. Fewer hydrophobic residues in small proteins reduce the intramolecular binding rate, resulting in the nucleation–condensation mechanism. Thus, the folding and binding of globular proteins and IDPs obey the same general principle, suggesting that the coarse-grained, statistical mechanical model of protein folding is promising for a unified theoretical description of all mechanisms.

Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell

“…It has been reported that 94 disordered regions have many post-translational modification sites (PTMs) [8,29,[39][40][41], which 95 induce conformational changes leading to one-lock-many-keys interactions [33]. A recent study 96 reviews different interaction mechanisms for unfolded and folded proteins [34]. Unfolded Many studies aiming at a general classification of IDPs' functional roles were based on the required 103 presence of long disordered regions in the sequence [18][19][20][42][43][44][45].…”

Structural metamorphism and polymorphism in proteins on the brink of thermodynamic stability

“…In many other cases, however, IDP binding is shown to be consistent with an induced fit mechanism where the polypeptide chain folds on the ligand surface . Such a mechanism seems to be more prevalent when the bound state of the IDP does not correspond with a globular structure …”

“…Similar to the fold switching examples discussed above, many IDPs are known to undergo significant conformational ordering upon binding to a ligand. There are numerous examples of such coupled folding and binding . In some cases, where the disordered protein is on the edge of being a globular fold, the binding affinity is related to its thermodynamic stability, suggesting a conformational selection mechanism analogous to the equilibrium shifts inferred in protein fold switches.…”

“…There are numerous examples of such coupled folding and binding. 21,[73][74][75][76][77][78][79] In some cases, where the disordered protein is on the edge of being a globular fold, the binding affinity is related to its thermodynamic stability, suggesting a conformational selection mechanism analogous to the equilibrium shifts inferred in 29 Salt, temperature 1J8I (monomer) 2JP1 (dimer) Chloride ion channel protein 30 Redox 1K0M (reduced) 1RK4 (oxidized) Mad2 spindle checkpoint protein 31 Ligand binding 1DUJ (inactive) 1S2H (active) T7 RNA polymerase 32,33 Ligand binding 1QLN (initiation) 1MSW (elongation) Viral fusion proteins 34,35 pH 5HMG (pre-fusion) (e.g., influenza virus hemagglutinin) 1HTM (post-fusion) P1 Lysozyme 36 Redox 1XJU (inactive) 1XJT (active) Circadian clock protein KaiB 37,38 Ligand binding 2QKE (inactive) 5JWR (active) RFaH C-terminal domain (CTD) 39,40 Ligand binding 2OUG (full length) 2LCL (CTD) Selecase 41 Concentration 4QHF (active) 4QHH (inactive) Cytolysin A 42 Membrane insertion 1QOY (monomer) 2WCD (protomer) Phytochromes 43,44 Light 4O0P (dark) 4O01 (light) Retinoic acid receptor 45 Ligand binding 1DKF (antagonist) 3KMR (agonist) TCR ectodomain 46 Unknown 2VLM (typical) 3MFF (alternative) Caspase-6 47 Ligand binding 2WDB (free) 3OD5 (bound) XRCC1 48 Redox 1XNT (reduced) 3LQC (oxidized) protein fold switches. This is clearly demonstrated in the complex of subtilisin with its N-terminal prodomain.…”

“…[81][82][83] Such a mechanism seems to be more prevalent when the bound state of the IDP does not correspond with a globular structure. 79 In addition to the use of mutations, IDP binding affinities can also be modulated by PTMs. One of the most common PTMs, phosphorylation, can alter charge distribution and provide new sites for hydrogen bonding interactions.…”