Electrostatically accelerated coupled binding and folding of intrinsically disordered proteins.
Intrinsically disordered proteins (IDPs) are now recognized to be prevalent in biology, and many potential functional benefits have been discussed. However, the frequent requirement of peptide folding in specific interactions of IDPs could impose a kinetic bottleneck, which could be overcome only by efficient folding upon encounter. Intriguingly, existing kinetic data suggest that specific binding of IDPs is generally no slower than that of globular proteins. Here, we exploited the cell cycle regulator p27(Kip1) (p27) as a model system to understand how IDPs might achieve efficient folding upon encounter for facile recognition. Combining experiments and coarse-grained modeling, we demonstrate that long-range electrostatic interactions between enriched charges on p27 and near its binding site on cyclin A not only enhance the encounter rate (i.e., electrostatic steering) but also promote folding-competent topologies in the encounter complexes, allowing rapid subsequent formation of short-range native interactions en route to the specific complex. In contrast, nonspecific hydrophobic interactions, while hardly affecting the encounter rate, can significantly reduce the efficiency of folding upon encounter and lead to slower binding kinetics. Further analysis of charge distributions in a set of known IDP complexes reveals that, although IDP binding sites tend to be more hydrophobic compared to the rest of the target surface, their vicinities are frequently enriched with charges to complement those on IDPs. This observation suggests that electrostatically accelerated encounter and induced folding might represent a prevalent mechanism for promoting facile IDP recognition.
Department of Biochemistry, Kansas State University, Manhattan, KS 66506, USA.
Debabani
D
Ganguly
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Steve
S
Otieno
The Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Brett
B
Waddell
Departments of Structural Biology and Developmental Neurobiology, St. Jude's Children's Research Hospital, Memphis, TN 38105, USA.
Luigi
L
Iconaru
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Richard W
RW
Kriwacki
Department of Biochemistry, Kansas State University, Manhattan, KS 66506, USA. Electronic address: jianhanc@ksu.edu.
Jianhan
J
Chen
D000595:Amino Acid Sequence; D019925:Cyclin A / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000737:chemistry* / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D055672:Static Electricity
D019925:Cyclin A; D050760:Cyclin-Dependent Kinase Inhibitor p27