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. 2020 May 22;8:e9197. doi: 10.7717/peerj.9197

Table 2. In silico analysis of 42 deleterious mutations in Rad50.

Amino acid impact (PredictSNP) (neutral/deleterious) Molecular mechanisms (MutPred2) Structural phenotyping (SNPeffect) Protein stability (imutant/MuPro)
Motif Mutation (source) PS MP Ph-S PP-1 PP-2 SF SP Affected molecular mechanisms Pr P-value Affected functional sites AG AM IM MPr
Walker A N38A (De La Rosa & Nelson, 2011) D D D D D D D Loss of catalytic site at N38 0.53 8.80E−05 • ATP/GTP-binding site motif A (P-loop) No No ↓ ↓
Loss of relative solvent accessibility 0.34 3.40E−03
Altered ordered interface 0.33 9.90E−03
Loss of allosteric site at N38 0.31 3.00E−03
Altered DNA binding 0.25 6.70E−03
Altered metal binding 0.23 0.02
Gain of methylation at K42 0.17 8.40E−03
G41D (Alani, Padmore & Kleckner, 1990) D D D D D D D Altered metal binding 0.40 1.70E−04 • FHA phosphopeptide ligands No No ↓ ↓
Gain of allosteric site at G41 0.33 6.40E−04 • CK2 Phosphorylation site
Altered ordered interface 0.30 0.02 • N-myristoylation site
Gain of relative solvent accessibility 0.29 0.01 • ATP/GTP-binding site motif A (P-loop)
Gain of helix 0.29 0.01
Loss of strand 0.28 9.70E−03
Altered DNA binding 0.28 4.30E−03
Loss of catalytic site at N38 0.27 3.70E−03
Loss of methylation at K42 0.17 0.01
K42R (Chen et al., 2005; Koroleva et al., 2007) D D D D D D D Loss of relative solvent accessibility 0.30 9.60E−03 • FHA phosphopeptide ligands No No ↓ ↓
Altered DNA binding 0.28 3.20E−03 • PKA phosphorylation site
Loss of allosteric site at T44 0.28 7.30E−03 • CK2 phosphorylation site
Loss of catalytic site at N38 0.27 3.40E−03 • N-myristoylation site
Altered metal binding 0.25 0.01 • ATP/GTP-binding site motif A (P-loop)
Loss of methylation at K42 0.20 6.90E−03
K42M (Koroleva et al., 2007) D D D D D D D Altered DNA binding 0.37 7.10E−04 • FHA phosphopeptide ligands No No ↑ ↑
Loss of allosteric site at K42 0.36 1.10E−03 • CK2 phosphorylation site
Loss of relative solvent accessibility 0.34 3.10E−03 • N-myristoylation site
Altered ordered interface 0.32 0.01 • ATP/GTP-binding site motif A (P-loop)
Gain of catalytic site at T43 0.29 1.60E−03
Altered metal binding 0.28 5.80E−03
Loss of methylation at K42 0.20 6.80E−03
K42E (Alani, Padmore & Kleckner, 1990; Chen et al., 2005) D D D D D D D Altered metal binding 0.44 4.50E−04 • FHA phosphopeptide ligands No No ↓ ↓
Gain of catalytic site at T43 0.33 6.40E−04 • CK2 phosphorylation site
Altered DNA binding 0.33 1.30E−03 • Polo-like kinase phosphorylation sit
Loss of allosteric site at K42 0.30 4.30E−03 • N-myristoylation site
Altered ordered interface 0.29 0.02 • ATP/GTP-binding site motif A (P-loop)
Loss of relative solvent accessibility 0.29 0.01
Gain of strand 0.27 0.03
Loss of methylation at K42 0.20 6.80E−03
K42A (Chen et al., 2005) D D D D D D D Loss of allosteric site at K42 0.53 5.40E−05 • FHA phosphopeptide ligands No No ↓ ↓
Loss of relative solvent accessibility 0.37 1.60E−03 • CK2 phosphorylation site
Altered DNA binding 0.37 6.00E−04 • N-myristoylation site
Altered ordered interface 0.36 4.20E−03 • ATP/GTP-binding site motif A (P-loop)
Gain of catalytic site at T43 0.32 8.70E−04
Altered metal binding 0.31 0.01
Loss of methylation at K42 0.20 6.80E−03
Q-loop Q159H (Moncalian et al., 2004) D D D D D D D No effect – – None No No ↓ ↓
Zinc hook S635G (Gatei et al., 2011) N N N D N N N No effect – – None No No ↓ ↓
S679R (Roset et al., 2014; Hohl et al., 2015) N N N N N D N No effect – – None No No ↓ ↓
C680N (He et al., 2012) N N N D N D D Loss of N-linked glycosylation at N677 0.02 0.04 • N-glycosylation site No No ↓ ↓
C681A (He et al., 2012) D D D D D D D Gain of helix 0.30 8.00E−03 • N-glycosylation site No No ↓ ↓
Gain of N-linked glycosylation at N677 0.02 0.03
C681S (Barfoot et al., 2015) D D D D D D N Gain of N-linked glycosylation at N677 0.02 0.04 • N-glycosylation site No No ↑ ↓
• Proline-directed phosphorylation
• MAPK phosphorylation site
P682E (Roset et al., 2014; Hohl et al., 2015) D D N D D D D Gain of helix 0.32 3.10E−03 • CK2 phosphorylation site No No ↓ ↓
Altered coiled coil 0.14 0.03
Loss of N-linked glycosylation at N677 0.02 0.04
P682A (He et al., 2012) N N N N D D N No effect – – None No No ↓ ↓
V683I (He et al., 2012) N N N N N D N No effect – – None No No ↑ ↑
V683R (Roset et al., 2014; Hohl et al., 2015) N N N N N D D Gain of helix 0.29 0.01 None No No ↓ ↓
C684R (He et al., 2012) D D D D D D D Gain of helix 0.30 9.50E−03 • Diarginine retention/retrieving signal No No ↓ ↓
C684S (Barfoot et al., 2015) D D D D D D D No effect – – • PIKK phosphorylation site No No ↓ ↓
• PKC phosphorylation site
Q685S (He et al., 2012) N N N N N D N Altered coiled coil 0.53 6.50E−03 • BRCT phosphopeptide ligands No No ↓ ↓
• USP7 binding motif
Signature motif R1198E (Rojowska et al., 2014) D D D D D D D Gain of catalytic site at R1200 0.25 4.80E−03 • Diarginine retention/retrieving signal No No ↓ ↓
Gain of allosteric site at R1200 0.21 0.03
Altered metal binding 0.14 0.03
Altered transmembrane protein 0.10 0.04
G1199E (Rojowska et al., 2014) D D D D D D D Loss of allosteric site at R1200 0.23 0.03 • Diarginine retention/retrieving signal No No ↓ ↓
Loss of catalytic site at R1200 0.20 0.01 • PKA phosphorylation site
Altered transmembrane protein 0.11 0.04
S1202A (Herdendorf & Nelson, 2011) D D D D D D D Loss of allosteric site at R1200 0.23 0.03 • PKA phosphorylation site No No ↓ ↓
Loss of catalytic site at R1200 0.20 0.01 • Glycosaminoglycan attachment site
S1202R (Koroleva et al., 2007; Moncalian et al., 2004; Herdendorf & Nelson, 2011; Bhaskara et al., 2007) D D D D D D D Gain of ADP-ribosylation at S1202 0.25 8.40E−03 • PKA phosphorylation site No No ↑ ↓
Loss of allosteric site at R1200 0.23 0.03 • Glycosaminoglycan attachment site
Loss of catalytic site at R1200 0.21 1.00E−02
S1202M (Herdendorf & Nelson, 2011) D D D D D D D Loss of allosteric site at R1200 0.23 0.02 • PKA phosphorylation site No No ↑ ↑
Gain of catalytic site at R1200 0.21 9.70E−03 • Glycosaminoglycan attachment site
Q1205E (Herdendorf & Nelson, 2011) D D D N D D D Gain of allosteric site at R1200 0.23 0.02 • PKA phosphorylation site ↑ ↓ ↓ ↓
Loss of catalytic site at R1200 0.20 0.01 • CK2 phosphorylation site
K1206M (Herdendorf & Nelson, 2011) D D D D D D D Gain of catalytic site at S1202 0.09 0.04 None ↑ ↓ ↑ ↑
K1206A (Williams et al., 2011) D D D D D D D Loss of catalytic site at K1206 0.09 0.05 None ↑ ↓ ↓ ↑
K1206E (Williams et al., 2011) D D D D D D D Gain of catalytic site at K1206 0.11 0.03 • TRAF2 binding site ↑ ↓ ↓ ↑
• NES nuclear export signal
L1211W (Deshpande et al., 2014) D D D D D D D Loss of catalytic site at K1206 0.08 0.05 • SUMO interaction site ↑ ↑ ↓ ↓
R1214A (Williams et al., 2011) D D D D D D D Loss of allosteric site at R1214 0.22 0.03 • ATP-binding cassette, ABC transporter-type, signature and profile ↑ ↓ ↓ ↓
R1214E (Deshpande et al., 2014; Williams et al., 2011) D D D D D D D Loss of allosteric site at R1214 0.20 0.04 • SUMO interaction site ↑ No ↓ ↓
• ATP-binding cassette, ABC transporter-type, signature and profile
Walker B E1232Q (Rojowska et al., 2014) D D D D D D D Altered metal binding 0.48 4.30E−03 • FHA phosphopeptide ligands No No ↓ ↓
Loss of catalytic site at E1232 0.34 9.80E−04 • SUMO interaction site
Loss of allosteric site at P1233 0.24 0.02
Altered transmembrane protein 0.12 0.03
D-loop D1238N (De La Rosa & Nelson, 2011) D D D D D D D Altered ordered interface 0.30 4.30E−03 • FHA phosphopeptide ligands No No ↓ ↓
Altered metal binding 0.31 2.80E−03 • Casein kinase II phosphorylation site
Gain of relative solvent accessibility 0.27 0.02
Gain of allosteric site at P1233 0.25 0.01
Loss of catalytic site at T1234 0.17 0.02
Altered transmembrane protein 0.12 0.03
Altered coiled coil 0.08 0.05
D1238A (De La Rosa & Nelson, 2011) D D D D D D D Altered metal binding 0.41 3.40E−04 • FHA phosphopeptide ligands No No ↓ ↓
Altered ordered interface 0.40 1.40E−03 • Casein kinase II phosphorylation site
Loss of allosteric site at P1233 0.26 0.01
Loss of catalytic site at T1234 0.18 0.02
Altered transmembrane protein 0.12 0.02
ATPase domain/coiled-coil K6E (Alani, Padmore & Kleckner, 1990; Bender et al., 2002) D D D D D N D Loss of strand 0.27 0.03 None No No ↓ ↓
Altered DNA binding 0.16 0.04
Gain of N-terminal acetylation at M1 0.03 4.10E−03
K22M (Alani, Padmore & Kleckner, 1990; Bender et al., 2002) N N N N N D N No effect – – None ↑ No ↓ ↑
R83I (Alani, Padmore & Kleckner, 1990; Bender et al., 2002) N D N N N D N Altered ordered interface 0.29 0.03 • PP1-docking motif RVXF ↑ ↑ ↓ ↑
Altered DNA binding 0.22 0.02
Altered coiled coil 0.10 0.04
K132E (Rojowska et al., 2014) D D N D D D D Loss of helix 0.28 0.02 • CK1 phosphorylation site No No ↓ ↓
Altered transmembrane protein 0.27 7.30E−04 • Protein kinase C phosphorylation site
Gain of strand 0.27 0.01
T191E (Rojowska et al., 2014) N D N N N N N Altered coiled coil 0.28 0.01 • TRAF2 binding site No No ↓ ↓
Loss of acetylation at K187 0.28 6.20E−03 • NEK2 phosphorylation site
• PKC phosphorylation site
C221E (Rojowska et al., 2014) N N N N N N N No effect – – None No No ↓ ↓
K105E (Rojowska et al., 2014) D N D D D D D No effect – – None No No ↓ ↓
S106E (Rojowska et al., 2014) N N N N N N N No effect – – None No No ↑ ↓

Note:

Different tools were used to analyze all mutations as abbreviated in the table. PS, PredictSNP; MP, MAPP; PhS, PhD-SNP; PP1, Poly-Phen1; PP2, Poly-Phen2; SF, SIFT; SN, SNAP; IM, I-Mutant; MPr, MuPro; Pr, probability; AG, protein aggregation; AM, Amyloid aggregation. Please refer to “Materials and Methods” for detailed descriptions of these tools. Note that all mutations listed above are based on the equivalent mutations in human.