Conserved Helix-Flanking Prolines Modulate Intrinsically Disordered Protein:Target Affinity by Altering the Lifetime of the Bound Complex

被引：37

作者：

Crabtree, Michael D. ^{[1
]}

Borcherds, Wade ^{[2
,3
]}

Poosapati, Anusha ^{[2
,3
]}

Shammas, Sarah L. ^{[1
,4
]}

Daughdrill, Gary W. ^{[2
,3
]}

Clarke, Jane ^{[1
]}

机构：

[1] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England

[2] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA

[3] Univ S Florida, Florida Ctr Drug Discovery & Innovat, Tampa, FL 33612 USA

[4] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England

来源：

BIOCHEMISTRY | 2017年 / 56卷 / 18期

基金：

美国国家卫生研究院; 英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

UNSTRUCTURED PROTEINS; IMPROVED SENSITIVITY; KIX DOMAIN; BINDING; SPECTROSCOPY;

D O I：

10.1021/acs.biochem.7b00179

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Appropriate integration of cellular signals requires a delicate balance of ligand target binding affinities. Increasing the level of residual structure in intrinsically disordered proteins (IDPs), which are overrepresented in these cellular processes, has been shown previously to enhance binding affinities and alter cellular function. Conserved proline residues are commonly found flanking regions of IDPs that become helical upon interacting with a partner protein. Here, we mutate these helix-flanking prolines in p53 and MLL and find opposite effects on binding affinity upon an increase in free IDP helicity. In both cases, changes in affinity were due to alterations in dissociation; not association, rate constants, which is inconsistent with conformational selection mechanisms. We conclude that, contrary to previous suggestions, helix-flanking prolines do not regulate affinity by modulating the rate of complex formation. Instead, they influence binding affinities by controlling the lifetime of the bound complex.

引用

页码：2379 / 2384

页数：6