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Table 1

Autoantigens Are Efficiently Cleaved by Granzyme B

No.AutoantigenCleavage sitekcat/Km
   M−1.s−1 
DNA-PKcs VGPD2,698-F 2.5 ± 0.8 × 106 
Topoisomerase I IEAD15-F 1.6 ± 0.6 × 106 
NuMA VATD1,705-A 5.4 ± 1.4 × 105 
Mi-2 VDPD1,312-Y 8.5 ± 1.9 × 104 
La LEED220-A 6.1 ± 1.7 × 104 
PMS1 ISAD496-E 6.9 ± 0.9 × 104 
Fibrillarin VGPD184-G 3.3 ± 1.9 × 104 
PARP VDPD536-S 2.3 ± 1.8 × 104 
U1-70kD LGND409-S 1.3 ± 0.4 × 104 
10 PMS2 VEKD493-S 1.4 ± 0.6 × 104 
11 Isoleucyl tRNA VTPD983-Q 7.8 ± 1.8 × 104 
 synthetase   
12 Histidyl tRNA LGPD48-E 2.3 ± 0.7 × 104 
 synthetase   
13 Alanyl tRNA VAPD632-R 1.8 × 104 
 synthetase   
14 RNA polymerase I ICPD448-M 1.3 ± 0.5 × 104 
15 Ki-67 VCTD1481-K 8.1 ± 2.6 × 103 
16 PMScl VEQD252-M 7.5 ± 1.4 × 103 
17 CENP-B VDSD457-E 5.9 ± 0.2 × 103 
18 RNA polymerase II ITPD370-P ND 
19 SRP-72 VTPD573-P ND 
20 Ku-70 ISSD79-R ND 
21 NOR-90 VRPD220-A ND 
No.AutoantigenCleavage sitekcat/Km
   M−1.s−1 
DNA-PKcs VGPD2,698-F 2.5 ± 0.8 × 106 
Topoisomerase I IEAD15-F 1.6 ± 0.6 × 106 
NuMA VATD1,705-A 5.4 ± 1.4 × 105 
Mi-2 VDPD1,312-Y 8.5 ± 1.9 × 104 
La LEED220-A 6.1 ± 1.7 × 104 
PMS1 ISAD496-E 6.9 ± 0.9 × 104 
Fibrillarin VGPD184-G 3.3 ± 1.9 × 104 
PARP VDPD536-S 2.3 ± 1.8 × 104 
U1-70kD LGND409-S 1.3 ± 0.4 × 104 
10 PMS2 VEKD493-S 1.4 ± 0.6 × 104 
11 Isoleucyl tRNA VTPD983-Q 7.8 ± 1.8 × 104 
 synthetase   
12 Histidyl tRNA LGPD48-E 2.3 ± 0.7 × 104 
 synthetase   
13 Alanyl tRNA VAPD632-R 1.8 × 104 
 synthetase   
14 RNA polymerase I ICPD448-M 1.3 ± 0.5 × 104 
15 Ki-67 VCTD1481-K 8.1 ± 2.6 × 103 
16 PMScl VEQD252-M 7.5 ± 1.4 × 103 
17 CENP-B VDSD457-E 5.9 ± 0.2 × 103 
18 RNA polymerase II ITPD370-P ND 
19 SRP-72 VTPD573-P ND 
20 Ku-70 ISSD79-R ND 
21 NOR-90 VRPD220-A ND 

Catalytic constant (kcat/Km) values were determined as described in Materials and Methods using defined amounts of purified granzyme B to cleave either radiolabeled substrates expressed by in vitro transcription/translation, endogenous substrates in cell lysates, or radiolabeled endogenous immunoprecipitated substrates. Likely granzyme B cleavage sites were predicted using fragment sizes and the known cleavage specificity of granzyme B 29,30. For autoantigens 1–10, the predicted cleavage sites were confirmed by showing that molecules having P1Asp→Ala substitutions were no longer cleaved by granzyme B (see Fig. 8).

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