Repository logo
 

Folding and binding pathways of BH3-only proteins are encoded within their intrinsically disordered sequence, not templated by partner proteins.

Published version
Peer-reviewed

Change log

Authors

Crabtree, Michael D 
Mendonça, Carolina ATF 
Bubb, Quenton R 

Abstract

Intrinsically disordered regions are present in one-third of eukaryotic proteins and are overrepresented in cellular processes such as signaling, suggesting that intrinsically disordered proteins (IDPs) may have a functional advantage over folded proteins. Upon interacting with a partner macromolecule, a subset of IDPs can fold and bind to form a well-defined three-dimensional conformation. For example, disordered BH3-only proteins bind promiscuously to a large number of homologous BCL-2 family proteins, where they fold to a helical structure in a groove on the BCL-2-like protein surface. As two protein chains are involved in the folding reaction, and the structure is only formed in the presence of the partner macromolecule, this raises the question of where the folding information is encoded. Here, we examine these coupled folding and binding reactions to determine which component determines the folding and binding pathway. Using Φ value analysis to compare transition state interactions between the disordered BH3-only proteins PUMA and BID and the folded BCL-2-like proteins A1 and MCL-1, we found that, even though the BH3-only protein is disordered in isolation and requires a stabilizing partner to fold, its folding and binding pathway is encoded in the IDP itself; the reaction is not templated by the folded partner. We suggest that, by encoding both its transition state and level of residual structure, an IDP can evolve a specific kinetic profile, which could be a crucial functional advantage of disorder.

Description

Keywords

B cell lymphoma 2 (Bcl-2) family, IDP, apoptosis, biophysics, coupled folding and binding, kinetics, protein folding, protein–protein interaction, thermodynamics, φ value

Journal Title

Journal of Biological Chemistry

Conference Name

Journal ISSN

1083-351X
1083-351X

Volume Title

293

Publisher

American Society for Biochemistry and Molecular Biology Inc.
Sponsorship
Wellcome Trust (095195/Z/10/Z)
Wellcome Trust (101474/Z/13/Z)