Mechanistic insights into poly(C)-binding protein hnRNP K resolving i-motif DNA secondary structures

Abstract

I-motifs are four-strand noncanonical secondary structures formed by cytosine (C)-rich sequences in living cells. The structural dynamics of i-motifs play essential roles in many cellular processes, such as telomerase inhibition, DNA replication, and transcriptional regulation. In cells, the structural dynamics of the i-motif can be modulated by the interaction of poly(C)-binding proteins (PCBPs), and the interaction is closely related to human health, through modulating the transcription of oncogenes and telomere stability. Therefore, the mechanisms of how PCBPs interact with i-motif structures are fundamentally important. However, the underlying mechanisms remain elusive. I-motif structures in the promoter of the c-MYC oncogene can be unfolded by heterogeneous nuclear ribonucleoprotein K (hnRNP K), a PCBP, to activate its transcription. Here, we selected this system as an example to comprehensively study the unfolding mechanisms. We found that the promoter sequence containing 5 C-runs preferred folding into type-1245 to type-1234 i-motif structures based on their folding stability, which was further confirmed by single-molecule FRET. In addition, we first revealed that the c-MYC i-motif structure was discretely resolved by hnRNP K through two intermediate states, which were assigned to the opposite hairpin and neighboring hairpin, as further confirmed by site mutations. Furthermore, we found all three KH (hnRNP K homology) domains of hnRNP K could unfold the c-MYC i-motif structure, and KH2 and KH3 were more active than KH1. In conclusion, this study may deepen our understanding of the interactions between i-motifs and PCBPs and may be helpful for drug development. I-motifs are four-strand noncanonical secondary structures formed by cytosine (C)-rich sequences in living cells. The structural dynamics of i-motifs play essential roles in many cellular processes, such as telomerase inhibition, DNA replication, and transcriptional regulation. In cells, the structural dynamics of the i-motif can be modulated by the interaction of poly(C)-binding proteins (PCBPs), and the interaction is closely related to human health, through modulating the transcription of oncogenes and telomere stability. Therefore, the mechanisms of how PCBPs interact with i-motif structures are fundamentally important. However, the underlying mechanisms remain elusive. I-motif structures in the promoter of the c-MYC oncogene can be unfolded by heterogeneous nuclear ribonucleoprotein K (hnRNP K), a PCBP, to activate its transcription. Here, we selected this system as an example to comprehensively study the unfolding mechanisms. We found that the promoter sequence containing 5 C-runs preferred folding into type-1245 to type-1234 i-motif structures based on their folding stability, which was further confirmed by single-molecule FRET. In addition, we first revealed that the c-MYC i-motif structure was discretely resolved by hnRNP K through two intermediate states, which were assigned to the opposite hairpin and neighboring hairpin, as further confirmed by site mutations. Furthermore, we found all three KH (hnRNP K homology) domains of hnRNP K could unfold the c-MYC i-motif structure, and KH2 and KH3 were more active than KH1. In conclusion, this study may deepen our understanding of the interactions between i-motifs and PCBPs and may be helpful for drug development. In addition to duplex type, DNA can adopt some noncanonical structures, such as four-stand structure G-quadruplexes (1Hänsel-Hertsch R. Antonio M.D. Balasubramanian S. DNA G-quadruplexes in the human genome: Detection, functions and therapeutic potential.Nat. Rev. Mol. Cell Biol. 2017; 18: 279-284Crossref PubMed Scopus (545) Google Scholar) and i-motifs (2Abou Assi H. Garavís M. González C. Damha M.J. i-Motif DNA: structural features and significance to cell biology.Nucl. Acids Res. 2018; 46: 8038-8056Crossref PubMed Scopus (188) Google Scholar). Among these two structures, G-quadruplexes that form within guanine (G)-rich sequences have been well studied from many different perspectives (1Hänsel-Hertsch R. Antonio M.D. Balasubramanian S. DNA G-quadruplexes in the human genome: Detection, functions and therapeutic potential.Nat. Rev. Mol. Cell Biol. 2017; 18: 279-284Crossref PubMed Scopus (545) Google Scholar, 3Robinson J. Raguseo F. Nuccio S.P. Liano D. Di Antonio M. DNA G-quadruplex structures: more than simple roadblocks to transcription?.Nucl. Acids Res. 2021; 49: 8419-8431Crossref PubMed Scopus (64) Google Scholar, 4Lane A.N. Chaires J.B. Gray R.D. Trent J.O. Stability and kinetics of G-quadruplex structures.Nucl. Acids Res. 2008; 36: 5482-5515Crossref PubMed Scopus (558) Google Scholar). However, their complementary i-motif structures are comparatively less well studied. I-motif structures are formed from cytosine (C)-rich DNA sequences at acidic pH, held together by hemi-protonated C and neutral C base pairs (C:C+) (2Abou Assi H. Garavís M. González C. Damha M.J. i-Motif DNA: structural features and significance to cell biology.Nucl. Acids Res. 2018; 46: 8038-8056Crossref PubMed Scopus (188) Google Scholar). Moreover, at neutral pH, molecular crowding can facilitate the formation of i-motif structures, which is in keeping with the intracellular environment (5Rajendran A. Nakano S. Sugimoto N. Molecular crowding of the cosolutes induces an intramolecular i-motif structure of triplet repeat DNA oligomers at neutral pH.Chem. Commun. 2010; 46: 1299-1301Crossref PubMed Scopus (142) Google Scholar). In addition, the existence of i-motif DNA structures was revealed using in-cell NMR spectroscopy (6Dzatko S. Krafcikova M. Hänsel-Hertsch R. Fessl T. Fiala R. Loja T. et al.Evaluation of the stability of DNA i-motifs in the nuclei of living mammalian cells.Angew. Chem. Int. Ed. 2018; 57: 2165-2169Crossref PubMed Scopus (140) Google Scholar) and confirmed by an antibody fragment (7Zeraati M. Langley D.B. Schofield P. Moye A.L. Rouet R. Hughes W.E. et al.I-motif DNA structures are formed in the nuclei of human cells.Nat. Chem. 2018; 10: 631-637Crossref PubMed Scopus (319) Google Scholar) in cells. The structural dynamics of these motifs play key roles in many essential processes, such as telomerase inhibition, DNA replication, and transcriptional regulation (2Abou Assi H. Garavís M. González C. Damha M.J. i-Motif DNA: structural features and significance to cell biology.Nucl. Acids Res. 2018; 46: 8038-8056Crossref PubMed Scopus (188) Google Scholar). The nuclease hypersensitive element III1 is located in the upstream of the oncogene c-MYC P1 promoter and modulates most c-MYC transcription. It contains 27-bp G/C-rich DNA sequences and can form G-quadruplexes and i-motifs in vivo (8González V. Hurley L.H. The c-MYC NHE III1: function and regulation.Annu. Rev. Pharmacol. Toxicol. 2010; 50: 111-129Crossref PubMed Scopus (135) Google Scholar, 9Chaudhuri R. Bhattacharya S. Dash J. Bhattacharya S. Recent update on targeting c-MYC G-quadruplexes by small molecules for anticancer therapeutics.J. Med. Chem. 2021; 64: 42-70Crossref PubMed Scopus (45) Google Scholar). In recent years, G-rich strands that form G-quadruplexes (known as Pu27) have been well studied (9Chaudhuri R. Bhattacharya S. Dash J. Bhattacharya S. Recent update on targeting c-MYC G-quadruplexes by small molecules for anticancer therapeutics.J. Med. Chem. 2021; 64: 42-70Crossref PubMed Scopus (45) Google Scholar). Although the complementary C-rich strands (referred to as Py27) that form i-motifs can also modulate c-MYC expression (8González V. Hurley L.H. The c-MYC NHE III1: function and regulation.Annu. Rev. Pharmacol. Toxicol. 2010; 50: 111-129Crossref PubMed Scopus (135) Google Scholar), they are comparatively less well studied. The core of Py27 (termed Py25 in this study) contains 5 runs of cytosines: C-tracts 1, 2, 3, 4, and 5 (Fig. 1A). Whether type-1245 (10Simonsson T. Pribylova M. Vorlickova M. A nuclease hypersensitive element in the human c-myc promoter adopts several distinct i-tetraplex structures.Biochem. Biophys. Res. Commun. 2000; 278: 158-166Crossref PubMed Scopus (125) Google Scholar) or type-1234 (11Dai J. Hatzakis E. Hurley L.H. Yang D. I-motif structures formed in the human c-MYC promoter are highly dynamic-insights into sequence redundancy and I-motif stability.PLoS One. 2010; 5e11647Crossref Scopus (60) Google Scholar) is the major structure is the subject of controversy (Fig. 1B). The structures of i-motifs are dynamic in living cells (7Zeraati M. Langley D.B. Schofield P. Moye A.L. Rouet R. Hughes W.E. et al.I-motif DNA structures are formed in the nuclei of human cells.Nat. Chem. 2018; 10: 631-637Crossref PubMed Scopus (319) Google Scholar), and their structural dynamics regulate biological processes (2Abou Assi H. Garavís M. González C. Damha M.J. i-Motif DNA: structural features and significance to cell biology.Nucl. Acids Res. 2018; 46: 8038-8056Crossref PubMed Scopus (188) Google Scholar). Although the structural dynamics of i-motifs induced by environmental conditions such as and have been studied using and single-molecule A. A. et of i-motif within DNA and Acids Res. PubMed Scopus Google Scholar, S. A. into the folding of a i-motif DNA in at the single-molecule Chem. PubMed Scopus Google Scholar, the dynamics of I-motif DNA by in at acidic Scopus Google Scholar, J. S. T. M. T. intramolecular folding dynamics of i-motif Chem. PubMed Scopus Google Scholar), their dynamics in cells are modulated by i-motif proteins (2Abou Assi H. Garavís M. González C. Damha M.J. i-Motif DNA: structural features and significance to cell biology.Nucl. Acids Res. 2018; 46: 8038-8056Crossref PubMed Scopus (188) Google Scholar). that i-motifs can in cells (6Dzatko S. Krafcikova M. Hänsel-Hertsch R. Fessl T. Fiala R. Loja T. et al.Evaluation of the stability of DNA i-motifs in the nuclei of living mammalian cells.Angew. Chem. Int. Ed. 2018; 57: 2165-2169Crossref PubMed Scopus (140) Google Scholar, M. Langley D.B. Schofield P. Moye A.L. Rouet R. Hughes W.E. et al.I-motif DNA structures are formed in the nuclei of human cells.Nat. Chem. 2018; 10: 631-637Crossref PubMed Scopus (319) Google Scholar), the of these structures is However, at this is their unfolding by such as hnRNP S. Hurley L.H. The transcriptional between the i-motif and hnRNP is a molecular for of expression that can be modulated by small Chem. PubMed Scopus Google Scholar), hnRNP S. transcription form i-motif structures unfolded by heterogeneous ribonucleoprotein PubMed Scopus Google Scholar), H. F. H. et and i-motif structure are in transcriptional regulation of in Acids Res. 2017; 46: Scopus Google Scholar), and proteins A.N. proteins as of biological PubMed Scopus Google Scholar). Among the heterogeneous nuclear ribonucleoprotein K (hnRNP K), a PCBP, for its cellular can activate the transcription of oncogenes unfolding their promoter such as P. R. Yang D. Hurley L.H. into the of the i-motif and G-quadruplex DNA structures formed in the promoter and Chem. 2017; PubMed Scopus Google Scholar) and c-MYC T. D. transcription from S. A. PubMed Scopus Google Scholar, M. T. M. M. H. et of heterogeneous ribonucleoprotein K to the human c-myc in Biol. Chem. PubMed Google Scholar), and may modulate telomere stability by i-motifs E. M. H. et of two human nuclear proteins that the of human in Acids Res. 2000; PubMed Scopus Google Scholar, D. P. J. et of human telomere DNA containing base Acids Res. 2018; 46: PubMed Scopus Google Scholar). However, the molecular of how hnRNP K i-motif structures to the of hnRNP K contains three KH (hnRNP K homology) domains (Fig. that the of i-motif structures D. Molecular of DNA by KH structure of a between hnRNP K KH3 and J. PubMed Scopus Google Scholar, M. S. and NMR of the KH of hnRNP K in with PubMed Scopus Google Scholar, T. D. nuclear ribonucleoprotein K is a Biol. Chem. PubMed Scopus Google Scholar). structural have that KH3 to or D. Molecular of DNA by KH structure of a between hnRNP K KH3 and J. PubMed Scopus Google Scholar, M. S. and NMR of the KH of hnRNP K in with PubMed Scopus Google Scholar). have that the can also sequences T. D. nuclear ribonucleoprotein K is a Biol. Chem. PubMed Scopus Google Scholar). However, all three of these motifs can i-motif structures and which the most the interaction of hnRNP K with i-motifs helpful for understanding this biological and also be for the molecular mechanisms of KH containing PCBPs A.N. proteins as of biological PubMed Scopus Google Scholar, R. S. H. et structure of the first KH of human poly(C)-binding in with a C-rich of human DNA at Biol. Chem. PubMed Scopus Google Scholar). In this hnRNP K was selected as an example to the molecular of i-motif were to the folding of and different that the type-1245 i-motif be the major of which was further confirmed by single-molecule was confirmed that hnRNP K could the Py25 i-motif using an and the folding and were using was revealed that all three of the KH domains were to unfold Py25 i-motif structure, and KH2 was the most study on the interactions between PCBPs and i-motif is fundamentally to the folding structure of Py25 to its The G-rich of the c-MYC promoter that G-quadruplexes been well and and type-1245 c-MYC G-quadruplexes are two major structures A. Hurley L.H. for a G-quadruplex in a promoter and its targeting with a small to c-MYC S. A. PubMed Scopus Google Scholar, H. J. F. J. Stability and kinetics of c-MYC promoter G-quadruplexes studied by single-molecule Chem. PubMed Scopus Google Scholar). Therefore, complementary type-1234 and type-1245 i-motifs were to be the major folding type-1245 or type-1234 is the structure (10Simonsson T. Pribylova M. Vorlickova M. A nuclease hypersensitive element in the human c-myc promoter adopts several distinct i-tetraplex structures.Biochem. Biophys. Res. Commun. 2000; 278: 158-166Crossref PubMed Scopus (125) Google Scholar, J. Hatzakis E. Hurley L.H. Yang D. I-motif structures formed in the human c-MYC promoter are highly dynamic-insights into sequence redundancy and I-motif stability.PLoS One. 2010; 5e11647Crossref Scopus (60) Google Scholar). type-1245 or type-1234 was the major folding structure (Fig. the C in Py25 was to to and they were to as and (Fig. 1A). folding was at different (Fig. as was the the stability of i-motifs J. S. T. M. T. intramolecular folding dynamics of i-motif Chem. PubMed Scopus Google Scholar). The of and that at were i-motif structures, at a i-motif was a at and a at (5Rajendran A. Nakano S. Sugimoto N. Molecular crowding of the cosolutes induces an intramolecular i-motif structure of triplet repeat DNA oligomers at neutral pH.Chem. Commun. 2010; 46: 1299-1301Crossref PubMed Scopus (142) Google Scholar). that type-1245 and type-1234 form i-motif structures at type-1245 or type-1234 was the structure, this study first their using the at and (Fig. The of that type-1245 was more than more on these the type-1245 i-motif be the major of was with a in which the of type-1234 was than that of type-1245 (11Dai J. Hatzakis E. Hurley L.H. Yang D. I-motif structures formed in the human c-MYC promoter are highly dynamic-insights into sequence redundancy and I-motif stability.PLoS One. 2010; 5e11647Crossref Scopus (60) Google Scholar). The between these two was that the study the of with the study the The of the in the study may have its stability, as in the of G-quadruplexes S. F. et human telomerase G-quadruplex and induces its distinct Chem. 2021; PubMed Scopus Google Scholar, D. J. et into the structural dynamics and unfolding of Biol. Chem. PubMed Scopus Google Scholar). The in the study the of our are more further the which can be to the folding and of DNA secondary structures through the dynamics of I-motif DNA by in at acidic Scopus Google Scholar, D. J. et into the structural dynamics and unfolding of Biol. Chem. PubMed Scopus Google Scholar, A of a G-quadruplex DNA the dynamics of and Biol. Chem. PubMed Scopus Google Scholar, J. D. T. in human S. A. PubMed Scopus Google Scholar), was was by a at the and its was with a complementary by at the and a at the from the and can the in i-motif structures the the dynamics of I-motif DNA by in at acidic Scopus Google Scholar, D. J. et into the structural dynamics and unfolding of Biol. Chem. PubMed Scopus Google Scholar, A of a G-quadruplex DNA the dynamics of and Biol. Chem. PubMed Scopus Google Scholar, J. D. T. in human S. A. PubMed Scopus Google Scholar). and containing were to as and (Fig. The was to the on the in pH, i-motif structures (Fig. to the of (Fig. S. A. into the folding of a i-motif DNA in at the single-molecule Chem. PubMed Scopus Google Scholar). Therefore, a of to to the and of and to i-motif structures, with a recent S. A. into the folding of a i-motif DNA in at the single-molecule Chem. PubMed Scopus Google Scholar). on the of the further the the the the structures of with that of (Fig. the i-motif structure in was from with the between and in is than that in to a Therefore, was to that Py25 was into the structure of type-1245 of type-1234 based on the of the In addition, the and were (Fig. to the for and folding (Fig. and their different from to are in on the of is that the of and be to that of and the of be than that of of the The were in with this the folding was that folding was than that of (Fig. In addition, was based on its than that of and Therefore, we that type-1245 is the most the major structure of this study to how proteins in cells unfolded this PCBPs have been to play essential roles in i-motif Among hnRNP K is in c-MYC i-motif unfolding through to the C-rich T. D. transcription from S. A. PubMed Scopus Google Scholar). However, the unfolding dynamics have elusive. study first and hnRNP K to (Fig. the of hnRNP K to was using (Fig. The was all was by hnRNP Therefore, were selected for hnRNP K could unfold the c-MYC i-motif in this system at were using a at and the of were different of hnRNP K from to (Fig. The of and and It was that at of hnRNP the from to in the of the and that the Py25 i-motif structure was unfolded by hnRNP The in and in confirmed that the from i-motif structure unfolding and or some mechanisms. a such as (Fig. the as the hnRNP K Furthermore, the of at different of hnRNP K were using to the (Fig. It was found that the the the the (Fig. and further the and dynamics of hnRNP K unfolding Py25 i-motif structure, the was to the structural of in at of hnRNP K (Fig. the addition of hnRNP the (Fig. that the i-motif structure was The at were well using a (Fig. which is to dynamic at the the dynamics of I-motif DNA by in at acidic Scopus Google Scholar, D. J. et into the structural dynamics and unfolding of Biol. Chem. PubMed Scopus Google Scholar, A of a G-quadruplex DNA the dynamics of and Biol. Chem. PubMed Scopus Google Scholar, J. D. T. in human S. A. PubMed Scopus Google Scholar), in to hnRNP two of and were 5 to hnRNP as many as of at and were hnRNP were three states, and the at The of and at were assigned to unfolded and and Therefore, the two be the folding (referred to as and in Furthermore, were to the between these (Fig. are in and their are in the the and the unfolded further and into the i-motif structure, this study the interaction between hnRNP K and the conditions (Fig. the states, and were to of hnRNP K unfolding and small was that hnRNP K resolved more than and may have been by the hnRNP K may to this D. Molecular of DNA by KH structure of a between hnRNP K KH3 and J. PubMed Scopus Google Scholar, M. S. and NMR of the KH of hnRNP K in with PubMed Scopus Google Scholar) to the of the i-motif this study to which structures the intermediate on the of i-motifs (Fig. could be that the intermediate the of The KH can D. Molecular of DNA by KH structure of a between hnRNP K KH3 and J. PubMed Scopus Google Scholar, M. S. and NMR of the KH of hnRNP K in with PubMed Scopus Google Scholar, R. S. H. et structure of the first KH of human poly(C)-binding in with a C-rich of human DNA at Biol. Chem. PubMed Scopus Google Scholar). Therefore, was that the be different of The i-motif structure of two opposite hairpin structures (Fig. 1B). a hnRNP K more (Fig. and It was that the be an opposite hairpin, from the of hnRNP K to of the opposite hairpin and the was the between the two of this unfolded i-motif structure was to be than in the to a of and this was by to this intermediate structure, which can into opposite hairpin at most (Fig. the was less than (Fig. the of three at and (Fig. C and in with the in the (Fig. C and and A and the that the was an opposite hairpin, and the further that i-motif structures and this study to the was assigned was found in hnRNP K unfolding (Fig. and the dynamics of (Fig. In addition to opposite runs may also into neighboring which may form of the opposite hairpin is further by a KH It was that the of neighboring this this study further of the opposite hairpin (Fig. and two that were and (Fig. more was the two of the be further than in the (Fig. in a at of these could into two at and (Fig. with the in the (Fig. and (Fig. C and and can into neighboring this confirmed the of was a neighboring hairpin, and the was further to be an opposite the hnRNP K the two opposite of the i-motif were and the neighboring an to in a in the of the and a in the of the (Fig. Therefore, this was In addition, the between opposite and neighboring were from and The intermediate were also in at (Fig. Therefore, i-motif opposite and neighboring were (Fig. of hnRNP K unfolding i-motif The processes i-motif structures, opposite neighboring and unfolded to the of and are by hnRNP heterogeneous nuclear ribonucleoprotein In A. A. et of i-motif within DNA and Acids Res. PubMed Scopus Google Scholar, S. A. into the folding of a i-motif DNA in at the single-molecule Chem. PubMed Scopus Google Scholar, J. S. T. M. T. intramolecular folding dynamics of i-motif Chem. PubMed Scopus Google Scholar) or the dynamics of I-motif DNA by in at acidic Scopus Google Scholar) intermediate were i-motif However, the of the study that were two the hnRNP K unfolding of the c-MYC i-motif In addition, the were assigned to the opposite and neighboring Therefore, be a between and hnRNP K contains three KH domains (Fig. that play a key in i-motif However, all three KH domains have unfolding and which KH is the most active remain these KH was and (Fig. and of KH was with (Fig. It was that the of the that all three KH domains were to unfold the i-motif structure (Fig. In addition, their were also well to using a (Fig. The were to the further that the was (Fig. the of the three KH the of the i-motifs based on the of at were using (Fig. A of a G-quadruplex DNA the dynamics of and Biol. Chem. PubMed Scopus Google Scholar, A. et the duplex and of a J. Biol. PubMed Scopus Google Scholar). are in on the of their and was the of KH2 was than that of with an in unfolding and were more active than based on the and in and In addition, the of KH was less than that of the hnRNP K the conditions (Fig. for and KH2 were that of the hnRNP K in of and at the interaction between KH and the i-motif could be to (Fig. were three for hnRNP K (Fig. the to the opposite hairpin further that hnRNP K was more The structural dynamics of i-motifs play a in Therefore, the molecular mechanisms of how proteins unfold i-motif structures is fundamentally However, this is selected the interaction between hnRNP K and c-MYC i-motif as an example to the molecular dynamic of how PCBPs unfold i-motif structures at the single-molecule and the unfolding In addition, the of all three KH domains of hnRNP K were The of this study be in understanding the cellular mechanisms of i-motif dynamics and in drug the formation of i-motif structures by (Fig. the type-1245 structure from was to be the major to Py25 sequences based on (Fig. was further confirmed by the of at the single-molecule (Fig. In addition, hnRNP K and further the that they have structures 5 and Therefore, was that was the i-motif structure of of may be to the major structures of The of hnRNP K to unfold the c-MYC i-motif structure was confirmed by a (Fig. the this first that hnRNP K resolved i-motif DNA discretely with opposite and neighboring as intermediate (Fig. which was further by and and the unfolding was (Fig. In addition, KH further this (Fig. deepen the understanding of how PCBPs unfold i-motif structures may also a for how proteins i-motif The of hnRNP K the c-MYC i-motif may more in cellular processes and may be in drug G-quadruplexes are also to two of which are and M. G-quadruplexes in different structural through different Acids Res. PubMed Scopus Google Scholar, R. J. T. DNA functions of on and G-rich Google Scholar). based on structural revealed the existence of the C. H. et structure of G-quadruplex formed by the and Acids Res. 2021; 49: PubMed Scopus Google Scholar), which could be from the opposite hairpin in the of their Whether is an intermediate for i-motif further the study the of all three KH domains (Fig. It was found that all three KH domains could i-motifs with that as KH2 KH3 (Fig. However, the KH domains were less active than hnRNP K (Fig. It been that KH3 of hnRNP K can and KH2 H. of the of KH domains different of different J. PubMed Scopus Google Scholar). Therefore, our on the between hnRNP K unfolding i-motif DNA and at the single-molecule of the at the pH, with and single-molecule the system and were of the DNA in this study are in the DNA of the of was the of the of and was to that the the structural states, and the was single-molecule the of to was to the that to the The of was of the was by at for 5 and to in the were on a that a and a cell D. J. et into the structural dynamics and unfolding of Biol. Chem. PubMed Scopus Google Scholar). 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