Id |
Subject |
Object |
Predicate |
Lexical cue |
T56 |
0-4 |
Sentence |
denotes |
2.2. |
T57 |
5-64 |
Sentence |
denotes |
Purification and In Vitro Characterization of PASylated Tα1 |
T58 |
65-284 |
Sentence |
denotes |
The uncharged PAS moiety, which does not alter the isoelectric point of the target peptide, facilitates classical protein precipitation by ammonium sulfate, thus providing an efficient and inexpensive purification step. |
T59 |
285-529 |
Sentence |
denotes |
After adjusting the cleared whole cell extract prepared by mechanical cell lysis to 30% ammonium sulfate saturation, most of the host cell proteins remained in solution while both PAS-Tα1 and PAS-Tα1 were selectively recovered as a precipitate. |
T60 |
530-696 |
Sentence |
denotes |
To remove residual E. coli proteins, the redissolved precipitate was subjected to ion exchange chromatography on a salt-tolerant anion exchange (AEX) resin at pH 8.5. |
T61 |
697-964 |
Sentence |
denotes |
Even though the PASylated Tα1 peptide with a calculated pI of 4.3 [38] for both versions should be negatively charged under these conditions and, hence, is expected to adsorb to the resin, the recombinant fusion proteins were quantitatively found in the flow-through. |
T62 |
965-1093 |
Sentence |
denotes |
Possibly, the voluminous PAS polymer partially shields the small peptide from ionic interactions with the chromatography matrix. |
T63 |
1094-1214 |
Sentence |
denotes |
Nevertheless, this step resulted in efficient depletion both of residual host cell proteins and of bacterial endotoxins. |
T64 |
1215-1496 |
Sentence |
denotes |
The protein solutions were dialyzed against a citrate buffer at pH 3.0 and subsequently applied to a strong cation exchange (CEX) column, which resulted in a bound fraction for PAS-Tα1, whereas both a flow-through fraction and a bound fraction were observed for Tα1-PAS (Figure 2). |
T65 |
1497-1745 |
Sentence |
denotes |
Electrospray ionization mass spectrometry (ESI-MS) analysis of Tα1-PAS in the flow-through revealed a molecular mass of 52,734.56 Da (Figure 2a), which exactly matches the calculated mass for the N-terminally acetylated gene product (52,734.56 Da). |
T66 |
1746-1950 |
Sentence |
denotes |
In this case, the start methionine of Tα1-PAS (followed by a Ser residue) was fully processed, presumably by the bacterial methionine aminopeptidase [39], then followed by N-terminal acetylation via RimJ. |
T67 |
1951-2302 |
Sentence |
denotes |
In contrast, the column-bound peptide fraction, which was eluted using a salt concentration gradient, showed a molecular mass of 52,692.38 Da (Figure 2b), which corresponds to the calculated mass for the non-acetylated processed polypeptide (52,692.54 Da) accompanied by some minor peaks below 40 kDa, most likely due to residual host cell impurities. |
T68 |
2303-2461 |
Sentence |
denotes |
Accordingly, this CEX step enabled separation of the desired N-acetylated Tα1-PAS from its non-acetylated precursor as a result of a single charge difference. |
T69 |
2462-2653 |
Sentence |
denotes |
In comparison, the fully column-bound non-acetylated PAS-Tα1 showed a single molecular mass of 52,789.8 Da (Figure 3) corresponding to the intact peptide, again, lacking the start methionine. |
T70 |
2654-2780 |
Sentence |
denotes |
Both PASylated peptide preparations had a purity > 96% as indicated by reverse-phase chromatography (Figure 2c and Figure 3c). |
T71 |
2781-2883 |
Sentence |
denotes |
For Tα1-PAS, we performed a final AEX polishing step, which also allowed concentration of the peptide. |
T72 |
2884-3010 |
Sentence |
denotes |
At pH 10, the acetylated Tα1-PAS bound to a strong AEX resin and eluted as a homogenous peak in a salt concentration gradient. |
T73 |
3011-3157 |
Sentence |
denotes |
The endotoxin content of this fraction was very low, with < 0.1 EU/mg, and the final yield was 15 mg acetylated Tα1-PAS per 1 L bacterial culture. |
T74 |
3158-3359 |
Sentence |
denotes |
In comparison, the final yield of the fully column-bound (non-acetylated) PAS-Tα1 reached 50 mg per 1 L bacterial culture after CEX chromatography and, again, the endotoxin content was below 0.1 EU/mg. |
T75 |
3360-3548 |
Sentence |
denotes |
Analytical size exclusion chromatography (SEC) of both PASylated peptide versions revealed a single symmetric peak without any signs of aggregation or truncation (Figure 2d and Figure 3d). |
T76 |
3549-3615 |
Sentence |
denotes |
The N-terminally acetylated Tα1-PAS eluted at 13.5 mL (bed volume: |
T77 |
3616-3737 |
Sentence |
denotes |
24 mL), whereas PAS-Tα1 eluted at 13.2 mL, thus indicating apparent molecular sizes of 557 kDa and 665 kDa, respectively. |
T78 |
3738-4048 |
Sentence |
denotes |
This is more than 10 times (Tα1-PAS) or even 12 times (PAS-Tα1) larger than the true molecular mass of both PASylated peptides (52.7 kDa), which demonstrates the huge expansion of the hydrodynamic molecular volume caused by the random-coil structure of the PAS polymer, in line with previous observations [35]. |