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Disordered Regions ...
Disordered Regions Flanking the Binding Interface Modulate Affinity between CBP and NCOA
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- Karlsson, Elin (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Schnatwinkel, Jan (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Ruhr Univ Bochum, Fac Chem & Biochem, Dept Phys Chem 1, D-44780 Bochum, Germany.
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- Paissoni, Cristina (author)
- Univ Milan, Dipartimento Biosci, I-20133 Milan, Italy.
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- Andersson, Eva (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Herrmann, Christian (author)
- Ruhr Univ Bochum, Fac Chem & Biochem, Dept Phys Chem 1, D-44780 Bochum, Germany.
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- Camilloni, Carlo (author)
- Univ Milan, Dipartimento Biosci, I-20133 Milan, Italy.
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- Jemth, Per (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- English.
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In: Journal of Molecular Biology. - : Elsevier. - 0022-2836 .- 1089-8638. ; 434:13
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Abstract
Subject headings
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- Recognition motifs that mediate protein-protein interactions are usually embedded within longer intrinsically disordered regions. While binding interfaces involving the recognition motif in such interactions are well studied, less is known about the role of disordered regions flanking the motifs. The interaction between the transcriptional co-activators NCOA3 (ACTR) and CBP is mediated by coupled binding and folding of the two domains CID and NCBD. Here, we used circular dichroism and kinetics to directly quantify the contribution of the adjacent flanking regions of CID to its interaction with NCBD. Using N-and C terminal combinatorial variants we found that the flanking regions promote binding in an additive fashion while retaining a large degree of disorder in the complex. Experiments at different ionic strengths demonstrated that the increase in affinity is not mediated by electrostatic interactions from the flanking regions. Instead, site-directed mutagenesis and molecular dynamics simulations suggest that binding is promoted by short-lived non-specific hydrophobic contacts between the flanking regions and NCBD. Our findings are consistent with highly frustrated interactions outside of the canonical binding interface resulting in a slightly energetically favorable fuzzy binding. Modulation of affinity via flanking regions could represent a general mechanism for functional regulation by intrinsically disordered protein regions.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- intrinsically disordered proteins
- flanking regions
- protein interactions
- affinity
- binding motif
Publication and Content Type
- ref (subject category)
- art (subject category)
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