The free energy folding penalty accompanying binding of intrinsically disordered α-helical motifs

Hadži, San (avtor), Lah, Jurij (avtor)

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes and preform critical roles in many cellular processes, most often through the association with globular proteins. Despite lacking a stable three-dimensional structure by themselves, they may acquire a defined conformation upon binding globular targets. The most common type of secondary structure acquired by these binding motifs entails formation of an α-helix. It has been hypothesized that such disorder-to-order transitions are associated with a significant free energy penalty due to IDP folding, which reduces the overall IDP-target affinity. However, the exact magnitude of IDP folding penalty in α-helical binding motifs has not been systematically estimated. Here, we report the folding penalty contributions for 30 IDPs undergoing folding-upon-binding and find that the average IDP folding penalty is +2.0 kcal/mol and ranges from 0.7 to 3.5 kcal/mol. We observe that the folding penalty scales approximately linearly with the change in IDP helicity upon binding, which provides a simple empirical way to estimate folding penalty. We analyze to what extent do prestructuring and target-bound IDP dynamics (fuzziness) reduce the folding penalty and find that these effects combined, on average, reduce the folding cost by around half. Taken together, the presented analysis provides a quantitative basis for understanding the role of folding penalty in IDP-target interactions and introduces a method estimate this quantity. Estimation and reduction of IDP folding penalty may prove useful in the rational design of helix-stabilized inhibitors of IDP-target interactions.

• Jezik: Angleški jezik
• Ključne besede: binding motif, folding penalty, folding-upon-binding, fuzziness, intrinsically disordered proteins, peptide inhibitor, pre-folding
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FKKT - Fakulteta za kemijo in kemijsko tehnologijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2022
• Št. strani: 11 str.
• Številčenje: Vol. 31, iss. 7, art. e4370
• PID: 20.500.12556/RUL-141972
• UDK: 577.322
• ISSN pri članku: 0961-8368
• DOI: 10.1002/pro.4370
• COBISS.SI-ID: 121839363
• Datum objave v RUL: 13.10.2022

Gradivo je del revije

• Naslov: Protein science
• Skrajšan naslov: Protein sci.
• Založnik: The Protein Society, Wiley
• ISSN: 0961-8368
• COBISS.SI-ID: 15692293

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: motiv vezanja, neugodno zvitje, zvitje ob vezanju, kaotičnost, intrinzično neurejeni proteini, peptidni inhibitor, predzvitje

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: J1-1706
• Naslov: Stabilnost nove vrste kvadruplesov DNA (AGCGA) in njihovo prepoznavanje z nanotelesi

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0201
• Naslov: Fizikalna kemija