Limitations of Induced Folding in Molecular Recognition by Intrinsically Disordered Proteins

ChemPhysChem ◽  
2009 ◽  
Vol 10 (9-10) ◽  
pp. 1415-1419 ◽  
Author(s):  
Eszter Hazy ◽  
Peter Tompa
Keyword(s):  
Molecular Recognition ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Induced Folding

scholarly journals Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

2019 ◽  
Vol 28 (11) ◽  
pp. 1952-1965 ◽  
Author(s):  
Jing Yang ◽  
Meng Gao ◽  
Junwen Xiong ◽  
Zhengding Su ◽  
Yongqi Huang
Keyword(s):  
Molecular Recognition ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals The mechanism of coupled folding-upon-binding of an intrinsically disordered protein

2020 ◽  
Author(s):  
Paul Robustelli ◽  
Stefano Piana ◽  
David E. Shaw
Keyword(s):  
Measles Virus ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Disordered Proteins ◽  
Binding Process ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Induced Folding ◽  
Helical Content ◽  
Intermolecular Contacts

AbstractIntrinsically disordered proteins (IDPs), which in isolation do not adopt a well-defined tertiary structure but instead populate a structurally heterogeneous ensemble of interconverting states, play important roles in many biological pathways. IDPs often fold into ordered states upon binding to their physiological interaction partners (a so-called “folding-upon-binding” process), but it has proven difficult to obtain an atomic-level description of the structural mechanisms by which they do so. Here, we describe in atomic detail the folding-upon-binding mechanism of an IDP segment to its binding partner, as observed in unbiased molecular dynamics simulations. In our simulations, we observed over 70 binding and unbinding events between the α-helical molecular recognition element (α-MoRE) of the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the measles virus phosphoprotein complex. We found that folding-upon-binding primarily occurred through induced-folding pathways (in which intermolecular contacts form before or concurrently with the secondary structure of the disordered protein)—an observation supported by previous experiments—and that the transition state ensemble was characterized by the formation of just a few key intermolecular contacts, and was otherwise highly structurally heterogeneous. We found that when a large amount of helical content was present early in a transition path, NTAIL typically unfolded, then refolded after additional intermolecular contacts formed. We also found that, among conformations with similar numbers of intermolecular contacts, those with less helical content had a higher probability of ultimately forming the native complex than conformations with more helical content, which were more likely to unbind. These observations suggest that even after intermolecular contacts have formed, disordered regions can have a kinetic advantage over folded regions in the folding-upon-binding process.

scholarly journals Designing heterotropically activated allosteric conformational switches using supercharging

2020 ◽  
Vol 117 (10) ◽  
pp. 5291-5297 ◽  
Author(s):  
Peter J. Schnatz ◽  
Joseph M. Brisendine ◽  
Craig C. Laing ◽  
Bernard H. Everson ◽  
Cooper A. French ◽  
...  
Keyword(s):  
Protein Function ◽  
Intrinsically Disordered Proteins ◽  
Control Mechanism ◽  
Divalent Cations ◽  
High Surface ◽  
Model Systems ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Low Concentrations

Heterotropic allosteric activation of protein function, in which binding of one ligand thermodynamically activates the binding of another, different ligand or substrate, is a fundamental control mechanism in metabolism and as such has been a long-aspired capability in protein design. Here we show that greatly increasing the magnitude of a protein’s net charge using surface supercharging transforms that protein into an allosteric ligand- and counterion-gated conformational molecular switch. To demonstrate this we first modified the designed helical bundle hemoprotein H4, creating a highly charged protein which both unfolds reversibly at low ionic strength and undergoes the ligand-induced folding transition commonly observed in signal transduction by intrinsically disordered proteins in biology. As a result of the high surface-charge density, ligand binding to this protein is allosterically activated up to 1,300-fold by low concentrations of divalent cations and the polyamine spermine. To extend this process further using a natural protein, we similarly modified Escherichia coli cytochrome b562 and the resulting protein behaves in a like manner. These simple model systems not only establish a set of general engineering principles which can be used to convert natural and designed soluble proteins into allosteric molecular switches useful in biodesign, sensing, and synthetic biology, the behavior we have demonstrated––functional activation of supercharged intrinsically disordered proteins by low concentrations of multivalent ions––may be a control mechanism utilized by Nature which has yet to be appreciated.

Disorder-function relationships for the cell cycle regulatory proteins p21 and p27

2012 ◽  
Vol 393 (4) ◽  
pp. 259-274 ◽  
Author(s):  
Diana M. Mitrea ◽  
Mi-Kyung Yoon ◽  
Li Ou ◽  
Richard W. Kriwacki
Keyword(s):  
Cell Division ◽  
Molecular Mechanisms ◽  
Intrinsically Disordered Proteins ◽  
Tertiary Structure ◽  
Structural Features ◽  
Disordered Proteins ◽  
Cellular Functions ◽  
Intrinsically Disordered ◽  
Induced Folding ◽  
Cell Cycle Regulatory Proteins

Abstract The classic structure-function paradigm has been challenged by a recently identified class of proteins: intrinsically disordered proteins (IDPs). Despite their lack of stable secondary or tertiary structure, IDPs are prevalent in all forms of life and perform myriad cellular functions, including signaling and regulation. Importantly, disruption of IDP homeostasis is associated with numerous human diseases, including cancer and neurodegeneration. Despite wide recognition of IDPs, the molecular mechanisms underlying their functions are not fully understood. Here we review the structural features and disorder-function relationships for p21 and p27, two cyclin-dependent kinase (Cdk) regulators involved in controlling cell division and fate. Studies of p21 bound to Cdk2/cyclin A revealed that a helix stretching mechanism mediates binding promiscuity. Further, investigations of Tyr88-phosphorylated p27 identified a signaling conduit that controls cell division and is disrupted in certain cancers. These mechanisms rely upon a balance between nascent structure in the free state, induced folding upon binding, and persistent flexibility within functional complexes. Although these disorder-function relationships are likely to be recapitulated in other IDPs, it is also likely that the vocabulary of their mechanisms is much more extensive than is currently understood. Further study of the physical properties of IDPs and elucidation of their links with function are needed to fully understand the mechanistic language of IDPs.

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