Intramolecular diffusion controls aggregation of the PAPf39 peptide

Srivastava, Kinshuk Raj; French, Kinsley C.; Tzul, Franco O.; Makhatadze, George I.; Lapidus, Lisa J.

doi:10.1016/j.bpc.2016.06.004

Cited by 12 publications

(7 citation statements)

References 27 publications

(30 reference statements)

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“…The ThT fluorescence curve resulted in a sigmoidal pattern with a prominent lag phase till 24 h corresponding to the nucleation stage, and was later followed by the exponential increase and plateau fluorescence representing oligomerization and fibril maturation, respectively. These aggregation kinetics appeared similar to the nucleation-dependent polymerization model for amyloidogenic proteins [32] as observed previously for PAP f39 aggregation [7,33,34,35].…”

Section: Resultssupporting

confidence: 84%

Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

et al. 2018

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PAP248–286, a 39 amino acid peptide fragment, derived from the prostatic acid phosphatase secreted in human semen, forms amyloid fibrils and facilitates the attachment of retroviruses to host cells that results in the enhancement of viral infection. Therefore, the inhibition of amyloid formation by PAP248–286 (termed PAP f39) may likely reduce HIV transmission in AIDS. In this study, we show that the naphthoquinone tryptophan (NQTrp) hybrid molecule significantly inhibited PAP f39 aggregation in vitro in a dose-dependent manner as observed from the ThT assay, ANS assay, and transmission electron microscopy imaging. We found that even at a sub-molar concentration of 20:1 [PAP f39:NQTrp], NQTrp could reduce >50% amyloid formation. NQTrp inhibition of PAP f39 aggregation resulted in non-toxic intermediate species as determined by the vesicle leakage assay. Isothermal titration calorimetry and molecular docking revealed that the binding of NQTrp and PAP f39 is spontaneous, and NQTrp predominantly interacts with the polar and charged residues of the peptide by forming hydrogen bonds and hydrophobic contacts with a strong binding energy. Collectively, these findings indicate that NQTrp holds significant potential as a small molecule inhibitor of semen amyloids.

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Section: Resultssupporting

confidence: 84%

Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

et al. 2018

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“…Although direct ion binding has been proposed to influence aSyn aggregation rates, the ion binding strength does not correlate with aggregation rates observed 33 IDPs rely on their ability to be highly dynamic and flexible to probe different conformational space allowing maintenance of their solubility and function. When the reconfiguration rates of the protein backbone are retarded this can lead to aggregation 17,[34][35][36][37][38] . For protein association and aggregation to occur, the proteins must firstly be in an aggregation prone conformation, and secondly must be stable for long enough for interactions to occur.…”

Section: Discussionmentioning

confidence: 99%

The role of water mobility in protein misfolding

Stephens

Kölbel

Moons

et al. 2021

Preprint

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The propensity for intrinsically disordered proteins to aggregate is heavily influenced by their surrounding environment. Here, we show that the mobility of the surrounding water molecules directly influences the aggregation rate of α-synuclein (aSyn), a protein associated with Parkinson’s disease. We observe that the addition of NaCl reduces the mobility of water, while addition of CsI increases the mobility of water. In turn, this reduces and increases the mobility of aSyn, respectively, given the change in strength and lifetime of the intermolecular forces. The reduction of aSyn mobility in the presence of NaCl ions leads to increased aggregation rates, which may be due to aggregation-competent conformations being stable for longer, thereby increasing the likelihood of establishing interactions between two adjacent monomers. In contrast, aSyn is more mobile when CsI is dissolved in the aqueous phase which leads to a reduction of successful monomeric interactions. We thus highlight the importance of the surrounding environment and describe how ion content can influence water mobility and the misfolding rate of amyloidogenic proteins, such as aSyn. By modulating the cellular environment to increase water mobility or finding small molecules to increase protein dynamics, new therapeutic targets may be found.

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“…Threonine may decrease D and therefore decrease the rate by increasing barriers to dihedral angle motion, and its bulkier side-chain compared to Ala could slow the rate by increasing r 2 . 27 Other interesting examples of using the technique of Trp-Cys contact quenching were the measurements of the rate of intramolecular contact in four different loops along the chain in α-synuclein, 29 in a fragment of human prostatic acidic phosphatase (PAP) showing that the full-length peptide diffuses much faster than the truncated peptide, 30 in protein L showing surprisingly low diffusion rates, 31,32 and in Syrian hamster and rabbit prion proteins at different pH values and concentration of denaturants. 33 The results presented above showed that some directly induced photochemical processes can be used for studying the kinetics of intramolecular-contact formation in peptides and proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Other interesting examples of using the technique of Trp-Cys contact quenching were the measurements of the rate of intramolecular contact in four different loops along the chain in α-synuclein, in a fragment of human prostatic acidic phosphatase (PAP) showing that the full-length peptide diffuses much faster than the truncated peptide, in protein L showing surprisingly low diffusion rates, , and in Syrian hamster and rabbit prion proteins at different pH values and concentration of denaturants …”

Section: Introductionmentioning

confidence: 99%

N-Terminal Decarboxylation as a Probe for Intramolecular Contact Formation in γ-Glu-(Pro)_n-Met Peptides

et al. 2020

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The kinetics of intramolecular-contact formation between remote functional groups in peptides with restricted conformational flexibility were examined using designed peptides with variable-length proline bridges. As probes for this motion, free radicals were produced using the • OH-induced oxidation at the C-terminal methionine residue of γ-Glu-(Pro) n -Met peptides ( n = 0–3). The progress of the radicals’ motion along the proline bridges was monitored as the radicals underwent reactions along the peptides’ backbones. Of particular interest was the reaction between the sulfur atom located in the side chain of the oxidized Met residue and the unprotonated amino group of the glutamic acid moiety. Interactions between them were probed by the radiation-chemical yields (expressed as G values) of the formation of C-centered, α-aminoalkyl radicals (αN) on the Glu residue. These radicals were monitored directly or via their reaction with p -nitroacetophenone (PNAP) to generate the optically detected PNAP •– radical anions. The yields of these αN radicals were found to be linearly dependent on the number of Pro residues. A constant decrease by 0.09 μM J –1 per spacing Pro residue of the radiation-chemical yields of G (αN) was observed. Previous reports support the conclusion that the αN radicals in these cases would have to result from (S∴N) + -bonded cyclic radical cations that arose as a result from direct contact between the ends of the peptides. Furthermore, by analogy with the rate constants for the formation of intramolecularly (S∴S) + -bonded radical cations in Met-(Pro) n -Met peptides ( 27513096 J. Phys. Chem. B 2016 120 9732 ), the rate constants for the formation of intramolecularly (S∴N) + -bonded radical cations are activated to the same extent for all of the γ-Glu-(Pro) n -Met peptides. Thus, the continuous decrease of G (αN) with the number of Pro residues (from 0 to 3) suggests that the formation of a contact between the S-atom in the C-terminal Met residue and the N-atom of a deprotonated N-terminal amino group of Glu is controlled in peptides with 0 to 3 Pro residues by the relative diffusion of the S •+ and unoxidized N-atom. The overall rate constants of cyclization to form the (S∴N)-bonded radical cations were estimated to be 3.8 × 10 6 , 1.8 × 10 6 , and 8.1 × 10 5 s –1 for peptides with n = 0, 1, and 2 Pro residues, respectively. If activation is the same for all of the peptides, then these rate constants are a direct indication for the end-to-end dynamics along the chain. ...

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Intramolecular diffusion controls aggregation of the PAPf39 peptide

Cited by 12 publications

References 27 publications

Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

The role of water mobility in protein misfolding

N-Terminal Decarboxylation as a Probe for Intramolecular Contact Formation in γ-Glu-(Pro)_n-Met Peptides

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Intramolecular diffusion controls aggregation of the PAPf39 peptide

Cited by 12 publications

References 27 publications

Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

Inhibitory Effect of Naphthoquinone-Tryptophan Hybrid towards Aggregation of PAP f39 Semen Amyloid

The role of water mobility in protein misfolding

N-Terminal Decarboxylation as a Probe for Intramolecular Contact Formation in γ-Glu-(Pro)n-Met Peptides

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N-Terminal Decarboxylation as a Probe for Intramolecular Contact Formation in γ-Glu-(Pro)_n-Met Peptides