Quantification of Conformational Entropy Unravels Effect of Disordered Flanking Region in Coupled Folding and Binding
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Quantification of Conformational Entropy Unravels Effect of Disordered Flanking Region in Coupled Folding and Binding. / Theisen, Frederik Friis; Staby, Lasse; Tidemand, Frederik Grønbæk; O'Shea, Charlotte; Prestel, Andreas; Willemoës, Martin; Kragelund, Birthe B.; Skriver, Karen.
In: Journal of the American Chemical Society, Vol. 143, No. 36, 2021, p. 14540-14550.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Quantification of Conformational Entropy Unravels Effect of Disordered Flanking Region in Coupled Folding and Binding
AU - Theisen, Frederik Friis
AU - Staby, Lasse
AU - Tidemand, Frederik Grønbæk
AU - O'Shea, Charlotte
AU - Prestel, Andreas
AU - Willemoës, Martin
AU - Kragelund, Birthe B.
AU - Skriver, Karen
PY - 2021
Y1 - 2021
N2 - Intrinsic disorder (ID) constitutes a new dimension to the protein structure-function relationship. The ability to undergo conformational changes upon binding is a key property of intrinsically disordered proteins and remains challenging to study using conventional methods. A 1994 paper by R. S. Spolar and M. T. Record presented a thermodynamic approach for estimating changes in conformational entropy based on heat capacity changes, allowing quantification of residues folding upon binding. Here, we adapt the method for studies of intrinsically disordered proteins. We integrate additional data to provide a broader experimental foundation for the underlying relations and, based on >500 protein-protein complexes involving disordered proteins, reassess a key relation between polar and nonpolar surface area changes, previously determined using globular protein folding. We demonstrate the improved suitability of the adapted method to studies of the folded aa-hub domain RST from radical-induced cell death 1, whose interactome is characterized by ID. From extensive thermodynamic data, quantifying the conformational entropy changes upon binding, and comparison to the NMR structure, the adapted method improves accuracy for ID-based studies. Furthermore, we apply the method, in conjunction with NMR, to reveal hitherto undetected effects of interaction-motif context. Thus, inclusion of the disordered context of the DREB2A RST-binding motif induces structuring of the binding motif, resulting in major enthalpy-entropy compensation in the interaction interface. This study, also evaluating additional interactions, demonstrates the strength of the ID-adapted Spolar-Record thermodynamic approach for dissection of structural features of ID-based interactions, easily overlooked in traditional studies, and for translation of these into mechanistic knowledge.
AB - Intrinsic disorder (ID) constitutes a new dimension to the protein structure-function relationship. The ability to undergo conformational changes upon binding is a key property of intrinsically disordered proteins and remains challenging to study using conventional methods. A 1994 paper by R. S. Spolar and M. T. Record presented a thermodynamic approach for estimating changes in conformational entropy based on heat capacity changes, allowing quantification of residues folding upon binding. Here, we adapt the method for studies of intrinsically disordered proteins. We integrate additional data to provide a broader experimental foundation for the underlying relations and, based on >500 protein-protein complexes involving disordered proteins, reassess a key relation between polar and nonpolar surface area changes, previously determined using globular protein folding. We demonstrate the improved suitability of the adapted method to studies of the folded aa-hub domain RST from radical-induced cell death 1, whose interactome is characterized by ID. From extensive thermodynamic data, quantifying the conformational entropy changes upon binding, and comparison to the NMR structure, the adapted method improves accuracy for ID-based studies. Furthermore, we apply the method, in conjunction with NMR, to reveal hitherto undetected effects of interaction-motif context. Thus, inclusion of the disordered context of the DREB2A RST-binding motif induces structuring of the binding motif, resulting in major enthalpy-entropy compensation in the interaction interface. This study, also evaluating additional interactions, demonstrates the strength of the ID-adapted Spolar-Record thermodynamic approach for dissection of structural features of ID-based interactions, easily overlooked in traditional studies, and for translation of these into mechanistic knowledge.
KW - INTRINSICALLY UNSTRUCTURED PROTEINS
KW - ACCESSIBLE SURFACE
KW - HEAT-CAPACITY
KW - WEB SERVER
KW - THERMODYNAMICS
KW - ENERGETICS
KW - COMPLEXES
KW - PEPTIDES
KW - NONPOLAR
KW - RESIDUES
U2 - 10.1021/jacs.1c04214
DO - 10.1021/jacs.1c04214
M3 - Journal article
C2 - 34473923
VL - 143
SP - 14540
EP - 14550
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 36
ER -
ID: 280733454