title: Binding and folding: in search of intramolecular chaperone-like building block fragments.
abstract: We propose an intramolecular chaperone which catalyzes folding and neither dissociates nor is cleaved. This uncleaved foldase is an intramolecular chain-linked chaperone, which constitutes a critical building block of the structure. Macroscopically, all molecular chaperones facilitate folding reactions and manifest similar energy landscapes. However, microscopically they differ. While intermolecular chaperones catalyze folding by unfolding misfolded conformations or prevent misfolding, the chain-linked cleaved (proregion) and uncleaved intramolecular chaperone-like building blocks suggested here, catalyze folding by binding to, stabilizing and increasing the populations of native conformations of adjacent building block fragments. In both, the more stable the intramolecular chaperone fragment region, the faster is the folding rate. Hence, mechanistically, intramolecular chaperones and chaperone-like segments are similar. Both play a dual role, in folding and in protein function. However, while the functional role of the proregions is inhibitory, necessitating their cleavage, the function of the uncleaved intramolecular chaperone-like building blocks does not require their subsequent removal. On the contrary, it requires that they remain in the structure. This may lead to the difference in the type of control they are under: proteins folding with the assistance of the proregion have been shown to be under kinetic control. It has been suggested that kinetically controlled folding reactions, with the proregion catalyst removed, lend longevity under harsh conditions. On the other hand, proteins with uncleaved intramolecular chaperone-like building blocks, with their 'foldases' still attached, are largely under thermodynamic control, consistent with the control observed in most protein folding reactions. We propose that an uncleaved intramolecular chaperone-like fragment occurs frequently in proteins. We further propose that such proteins would be prone to changing conditions and in particular, to mutations in this critical building block region. We describe the features qualifying it for its proposed chaperone-like role, compare it with inter- and intramolecular chaperones and review current literature in this light. We further propose a mechanism showing how it lowers the barrier heights, leading to faster folding reaction rates. Since these fragments constitute an intergal part of the protein structure, we call these critical building blocks intramolecular, chaperone-like fragments, to clarify, distinguish and adhere to the definition of the transiently associating chaperones. The new mechanism presented here differs from the concept of 'folding nuclei'. While the concept of folding nuclei focuses on a non-sequential distribution of the folding information along the entire protein chain, the chaperone-like building block fragments proposition focuses on a segmental distribution of the folding information. This segmental distribution controls the distributions of the populations throughout the hierarchical folding processes.
authors.affiliation: Laboratory of Experimental and Computational Biology and Intramural Research Support Program-SAIC, Laboratory of Experimental and Computational Biology, NCI-FCRDC, Bldg 469, Rm 151, Frederick, MD 21702, USA.
authors.forename: B
authors.initials: B
authors.lastname: Ma
authors.forename: C J
authors.initials: CJ
authors.lastname: Tsai
authors.forename: R
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D002384:Catalysis; D007700:Kinetics; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D018832:Molecular Chaperones; D010446:Peptide Fragments; D011506:Proteins; D013762:Tetrahydrofolate Dehydrogenase