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NMR spectroscopy Abstract Parvulins or rotamases form a distinct group within peptidyl prolyl cis-trans isomerases. Their exact mode of action as well as the role of conserved residues in the family are still not unambiguously resolved. The resulting ensembles are in good agreement with the experimental data but reveal important differences between the three enzymes.

The largest difference can be attributed to the extent of the opening of the substrate binding cleft, along which motional mode the three molecules occupy distinct regions. Comparison with a wide range of other available parvulin structures highlights structural divergence along the bottom of the binding cleft acting as a hinge during the opening-closing motion.

In the prototype WW-domain containing parvulin, Pin1, this region is also important in forming contacts with the WW domain known to modulate enzymatic activity of the catalytic domain. PPIases play an important role not only in protein folding but also in the regulation of several of biological processes like chromatin remodeling, transcription and nuclear receptor signaling 1.

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They can be divided into three non-homologous and structurally different families, known as cyclophilins, FKBPs FK binding protein and its relativesand parvulins. The latter, highly conserved subfamily consists of small ~10 kDa proteins that are present in both pro- and eukaryotes 2.

Their structure consists of a four-stranded antiparallel β-sheet surrounded by four α-helices αβ3βαβ2, parvulin fold 3. Parvulins play key roles in many important biological processes including the cell-cycle regulation, apoptosis and protein quality control 45. The two main classes of parvulins are the Pin1-type and non-Pin1-type parvulins.

Most of them, like their archetype Pin1, contain an N-terminal WW domain responsible for a ligand recognition and a conserved C-terminal PPIase domain with a phosphate-binding loop. Interestingly, there are some known members of the Pin1 family that do not possess a WW domain, i. In contrast, the non-Pin1-type parvulins are single domain proteins and their isomerization mechanism is phosphorylation-independent.

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Thus, the phosphate-binding site is missing, which is the only significant structural and functional difference green light laser prostate surgery forum the PPIase domain between the Pin1-type and non-Pin1-type parvulins. The exact mechanism of action of PPIases is not yet elucidated. It is unclear whether different PPIase families or distinct members within a family exhibit similar mechanisms.

However, it is generally accepted that there is no breaking and reforming of the peptide bond, thus, the bond is converted from the cis to the trans form via green light laser prostate surgery forum through a twisted amide intermediate In a recent study on cyclophilin A, dynamic structural ensembles were generated using chemical shift data for a structurally heterogeneous state where both the cis and trans isomer of the ligand are present.

Furthermore, although the active site of the parvulin-type PPIases is well-defined, the mechanistic role of the constituent residues is not yet fully clarified. The two highly conserved histidines of parvulin-type PPIases have been suggested to be important for catalysis. However, many His mutants krónikus prosztatitis mint a veszélyes partner Pin1 retained PPIase activity and, interestingly, the selectivity of Pin1 towards phosphorylated substrates was dependent on the identity of the replacing residues.

Circular dichroism investigations together with proteolytic susceptibility data led to the suggestion that the mutations influenced the dynamics of Pin1 rather than causing substantial structural rearrangements Replacing the threonine with alanine in Pin1 resulted in fold decrease in catalytic activity while not compromising structural integrity The aspartate is in a position occupied by a cysteine in Pin1, also suggested to be important in catalysis earlier Detailed theoretical studies hinted that this cysteine, through changes in its protonation state, can mediate dynamic changes in this network Indeed, replacing this cysteine with alanine or serine caused the disruption of the hydrogen bond between the histidines NMR analysis of conformational exchange in Pin1 suggested a link between motional modes present in the catalytic domain and the rate of catalysis, leading to the hypothesis that the internal motions assisting catalysis are an intrinsic Prosztate lebegése of Pin1 Ligand binding has been shown to influence the internal dynamics of Pin1, leading to more extensive contact between the PPIase and WW domains proposed to be linked to the loss of flexibility at specific conserved hydrophobic sites Specifically, changes in side-chain mobility upon ligand binding highlighted the role of an internal conduit consisting of hydrophobic side-chains.

These residues are conserved in Pin1 homologs and have been suggested to play an important role in inter-domain communication Molecular dynamics studies of Pin1 revealed allosteric pathways and suggested that substrate binding by the WW green light laser prostate surgery forum leads to preorganization of the catalytic site The range of identified residues participating in allosteric communication extends those revealed by NMR studies of side-chain flexibility Importantly, the preorganization was identified as a closure of the loop regions surrounding the substrate-binding cleft, and the presence of Vazectomia és prostatitis WW domain enhances the flexibility of these loops A recent study combining NMR spectroscopy and molecular dynamics indicated that the WW domain undergoes structural changes upon ligand binding and these changes affect its association with the PPIase domain in full-length Pin1, a mechanism proposed to inkontinencia kezelése lézerrel responsible for different activity of Pin1 on ligands with single and multiple recognition sites To get further insights to the differences between various parvulins, we have combined molecular dynamics simulations with experimentally available backbone S2 order parameters to conduct a comparative analysis of three single-domain parvulins.

SaPrsA from Staphylococcus aureus is responsible for folding of secreted proteins. Although member of a different subclass, its three-dimensional structure and active site arrangement proved to be almost the same as for human Pin1. The profound knowledge of histidine protonation states of His residues was investigated in detail experimentally obtained, revealing different tautomeric states for the two conserved histidines and the presence of a hydrogen bond between their side chains 26 and this is also reflected in the corresponding PDB structure id: 2JZV.

TbPin1 from Trypanosoma brucei is considered as a putative Pin1-type parvulin despite it lacks the WW domain It was shown that replacing Cys65 corresponding to Cys in Pin1 with Ala diminishes its catalytic activity, in accordance with other studies on the role of this residue see above. In the structures deposited in PDB id: 2LJ4 both His residues are protonated and there are no hydrogen bonds between them.

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CsPinA from the psychrophilic archaeon Cenarchaeum symbiosum has been shown to possess an atypically large peptide-binding site. The three investigated parvulins share a common structural core Fig. The smaller lobe, shown in the left of the figure and closer to the N-terminus, consists of a short helix and a loop structure, whereas the larger one is formed by a four-stranded antiparallel β-sheet and two helices located opposite the cleft.

The conserved histidines are located in the two central strands of the β-sheet.

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Notably, all residues forming the hydrogen-bonding network described above can be found in the large lobe Fig. Available backbone S2 order A megnyilvánulás prosztata jelei for the three molecules suggest some characteristic differences with TbPin1 showing the lowest average values Fig.

Top right: TbPin1 structure with the residues involved in the hydrogen-bonding network highlighted. Bottom: sequence alignment of the three parvulins with the residues involved in the hydrogen-bonding network highlighted.

Full size image Figure 2: Experimental S2 values for the three parvulins investigated. As a control, unrestrained ensembles were also generated see Methods for details. The MUMO and unrestrained ensembles contain conformers each. In the case of the MUMO ensembles, correspondence to S2 order parameters could be achieved without compromising the agreement with Cα and Hα chemical shifts that are most sensitive to protein structure Table 1.

The unrestrained ensembles, similarly to those deposited in the PDB, are not compatible with the backbone S2 data, as can be expected Table 1 Correspondence of the ensembles to experimental data.

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Full size table For CsPinA, the S2 value of the Green light laser prostate surgery forum residue, Gly97, had to be excluded from the backbone S2 correlation because of a conformational drift during the MD simulation resulting in two alternative orientations of this residue in the final ensemble.

Closer analysis hints that this might be the consequence of the NOE restraints in the region exclusion of all restraints violated in the PDB ensemble hinders the occurrence of the conformational drift.

However, as this region is not included in any of the consensus mappings, this does not affect any of our conclusions below. It should be noted that in our calculations NOE data were used to restrain the ensemble close to the native conformation, but, as in other ensembles reflecting multiple NMR-derived parameters, it can not be expected that all NOE restraints are fulfilled 30 This trend is more evident when only structurally equivalent residues, defined in the basis of a structural alignment of the three proteins see Methodsare considered.

Bottom panels C,F,I : PCA plots first two modes of the residues corresponding to the consensus mapping of the three proteins see Methods for details.

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Full size image The three parvulin ensembles differ in the extent of binding cleft opening The ensembles of the three different PPIase domains were compared using the set of residues that could be aligned in a multiple structural alignment see Methods.

The resulting mapping contains 89 residues including the substrate binding cleft and the two surrounding lobes Fig. The same remains mostly valid for the unrestrained ensembles Fig. Figure 4: Diversity of the ensembles using only the positions common to all three parvulins.

Closer analysis of this mode reveals that mode 1 in the MUMO ensembles reflect a motion roughly corresponding to the opening and closing of the substrate binding cleft and can be approximated by measuring the distance between residues near the tip of the two flanking loops of the cleft Fig.

Along this coordinate, the TbPin1 ensemble occupies the largest region, thus, our analysis suggests that this motion is primarily present in the TbPin1 ensemble but is also clearly present in SaPrsA.

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We have analyzed the residues involved in ligand binding and largely conserved in all three parvulins analyzed see Methods.

PCA analysis of selected heavy atoms is shown in Fig. PCA mode 1 largely describes the alterations of the distance of residues located at opposite sides of the binding cleft, most prominently those corresponding to Met and Cys in Pin1.

Thus, the differences observed in the binding sites can also mostly be attributed to the opening-closing motion separating the full structures in the MUMO ensembles.

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S2 restraining yields a conformational ensemble consistent with the fast ps-ns internal motions, thus, it is expected that the resulting ensemble samples the conformational space around an average structure representing the native state.

However, in the case of TbPin1, the nature of the conformational movements sampled, in particular the breathing motion, would be expected to occur on a slower time scale. Thus, we regard the generated ensembles as reflecting the upper limit of the conformational space sampled by the three parvulins during their fast motions.

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In this interpretation the ensembles do not necessarily reflect that the binding site opening - at least to the extent reflected by the TbPin1 ensemble - indeed occurs on such a fast time scale, although the correspondence to S2 order parameters strengthens the validity of larger motions in TbPin1 along this mode than in the other two parvulins.

In principle, S2 restraining does not necessarily restrict the extent of the motions sampled but limits primarily only their directions.

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Considering the results of PCA analysis it can be safely stated that its diversity is distributed along different internal motions than observed for the other two molecules. It should also be noted that for Pin1, conformational motions expected to be characteristic of slower time scales also occurred in a ns simulation As both Pin1 and TbPin1 act on phosphorylated substrates, this observation - relatively large amplitude motions of the binding cleft at a fast time scale - might even have relevance for this subtype of parvulins.

For TbPin1, NMR relaxation analysis revealed a group of residues with slow exchange located at the phosphate-binding loop, which might also indicate the presence of larger-scale opening-closing motions, although on a slower time scale.

Comparison with other parvulins highlights diversity in the hinge region To compare the ensembles with other parvulin domains of known structure, we have generated a consensus residue mapping between rotamase domains, including the representative structures of SaPrSA, TbPin1 and CsPinA, available in the PDB Supplementary Fig.

Interestingly, this consensus mapping contains only 53 residues including only one of the conserved histidine residues, as the one closer to the N-terminus is not part of this consensus. It is somewhat surprising that, contrary to expectations 3233the diversity of the MUMO ensembles is higher than that of the different PDB-derived parvulins.

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However, at least for structures determined with crystallography it is expected that the crowded environment of a crystal does not favor open conformations. Interestingly, the only group with a substantial distribution along this mode corresponds to the proteins with 2 rotamase domains Fig. We note that from these, only one available structure, 1m5y E. In this structure, the first N-terminally located parvulin domains are surrounded by an extension around the large lobe of the binding cleft.

B Displacements along PCA mode 1 dark green and 2 orange. Note that the residue numbering refers to the common positions comprising 53 residues only. Note that the parts retained based on the structure alignment contain only the two loops connected with the two peaks in PCA mode 1.

The WW is domain is in the back, colored light gray. The hinge region identified in PCA mode 1, defined by the minimum around residue 38 in the mapped numbering Gly in Pin1is mostly affected by displacements along PCA coordinate 2 Fig. Prostate cancer test the different parvulin ensembles are also separated along this motional mode, it is tempting to assume that they correspond to different states along a common motional mode occurring on a slower time scale and some of their functional differences can be explained by the differences required in their ligands to trigger proper binding and effective catalysis to green light laser prostate surgery forum.

However, whether larger-scale motions of this type occur in all molecules and whether they can be linked to any aspect of catalysis remains to be shown.

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Our first-approximation estimate of green light laser prostate surgery forum electrostatic field at the position of the carbonyl C of the isomerised amide bond of the substrate did not reveal any dependence on the extent of the opening of the binding cleft not shown.

However, the difference between the mode and extent of this opening motion between these molecules might still be valid and might influence their functional diversity. In Pin1, the WW domain exerts a significant influence on the catalytic properties: Both WW-deletion mutants and point mutants influencing the interaction between the WW and parvulin domains show markedly different activity relative to wild-type Pin1.

As the WW-parvulin interaction site is located on the side of the ligand-binding cleft, it can be speculated that the extent and mode of interaction with the WW domain modulates the breathing motion of the cleft, thereby contributing to the regulation of its enzymatic activity. This hypothesis is consistent with the recent molecular dynamics study of Pin1, where the presence of the WW domain enhanced the flexibility of the loops around the binding site 24 and also with the separation of the WW-containing and WW-less parvulins in our comparative PCA analysis.

These parvulins are separated along PCA mode 2 prosztata eltávolítás utáni impotencia to differences distributed near the bottom of the binding cleft, ideal in a position to modulate the flexibility of the parvulin domain. This is supported by our observation that the hinge region identified for the opening-closing motion displays the highest displacement in the PCA analysis of all PPIase domains with known structure Fig.

Thus, we hypothesize that changes in the hinge region, either caused by mutations or the interaction with the WW domain, if present, can influence the opening of the substrate binding cleft.

Indeed, residues adjacent to this putative hinge region have been shown to be influenced by mutations introduced into the WW domain of Pin1 Moreover, NMR relaxation analysis identified two residues in this region, Ile 98 and Asp according to residue numbering in 2LJ4 that are involved in slow conformational exchange Possible role of the conserved histidines and the hydrogen bond network In search for the factors that might influence the different preferences of the three parvulins with respect to the opening of the binding cleft, we performed detailed analysis of the conformation, possible pKa value distribution and hydrogen-bonding pattern of the conserved histidine residues.

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Both the conformation, as measured by the side-chain chi1 and chi2 green light laser prostate surgery forum and the distribution of the predicted pKa values are different in all three ensembles. It is important to note here that both TbPin1 and CsPinA were calculated with fully protonated histidine side chains, consistent with the PDB-deposited structures, whereas for SaPrsA the results of the detailed analysis published along with the structure green light laser prostate surgery forum were taken into account.

Thus, in SaPrsA there is a hydrogen bond between the two His residues that can not form in the two other parvulins due to the protonation state and conformation of the imidazole rings Fig. This is also reflected in the observation that the relative side-chain orientations of the histidine side chains are most restricted relative to each other in the SaPrsA ensemble Fig.

Figure 6 A Scheme of the residues involved in the proposed hydrogen bond network. The orientation of the histidines was taken from the first model of green light laser prostate surgery forum PDB-deposited ensembles.

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Residue numbering corresponds to that of the PDB ensembles. Hydrogen bonds detected in the MUMO ensembles are shown. Note that the occurrence of the individual hydrogen bonds varies in the ensembles.

B Chi1-Chi1 and Chi2-Chi2 differences between the two conserved histidines indicate different relative orientations of the side chains in the three ensembles. Overall, PCA coordinate 1 here shows a correlation of 0.

Full size image It should be noted that although the pKa values of histidine residues are conformation-dependent 34the pKa values predicted here probably overestimate the actual variability occurring during fast motions Fig.

Analysis of the CA positions of the residues involved in the putative hydrogen-bonding network suggest that there are motions confined within the large lobe that are at least weakly correlated with the breathing motion of the full parvulin molecules, again dominated by the motions TbPin1 Fig.

Although the two data sets are not independent i. Thus, changes in His protonation and thus the formation of the hydrogen bond might be one of the factors to be modulated by exact spatial context including substrate binding and interaction with the WW domain 23 Besides the formation of a hydrogen bond between the two imidazole moieties, His protonation also affects the conformational preferences of His residues that might provide even more subtle ways of regulation in this respect.

The lack of the hydrogen bond in TbPin1 and CsPinA is consistent with the observation that Pin1 histidine mutants were catalytically active 16 and supports the speculation that His protonation state can be a relevant factor in modulating activity.

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