Homology Modeling Study of Bovine μ-Calpain Inhibitor-Binding Domains
Abstract
:1. Introduction
2. Results
2.1. Structural Comparison between Active and Inactive Bovine CAPN1 Models
2.1.1. Comparison of the Large and Small Subunits in CAPN1 and CAPN2 Molecules
2.1.2. Evaluation of Homology Modeled Proteins
2.1.3. Overlay Structure Similarity Using Field-Based Alignment
2.1.4. Potential Functional Residues and Interaction Interfaces
2.1.5. Comparison of Ca2+-Binding Patterns in CAPN Subgroups
2.1.6. The Role of Structural Water Molecules for Their Ca2+-Binding Patterns
2.1.7. Structure Flexibility and Changes on CAPN Activation
2.2. A Structural Model for the Inhibition of CAPN1 by CAST4 from Both Bovines
2.2.1. Structure Modeling and Evaluation of the Bovine CAPN1/CAST4 Complex
2.2.2. Functional Characterization of the Inhibitory Motif of CAST4 Subdomain B
3. Discussion
4. Materials and Methods
4.1. A Structural Model of the Bovine CAPN1 Protein in the Absence of Calcium
4.2. Predicting the Complex Structure between Calcium Bound, Bovine CAPN1 and CAST
5. Conclusions
Acknowledgments
Conflicts of Interest
References
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CAPN1 vs. Bovine | Sequence identity (%) | ||||
---|---|---|---|---|---|
Domain I (DI) | Domain II (DII) | Domain III (DIII) | Domain IV (DIV) | Overall * | |
House mouse | 91.6 | 85.5 | 87.3 | 93.6 | 89.5 |
Norway rat | 91.6 | 84.9 | 87.3 | 93.6 | 89.7 |
Dog | 95.3 | 91.0 | 94.3 | 97.7 | 94.7 |
Rhesus monkey | 94.8 | 93.4 | 93.6 | 98.3 | 95.1 |
Human | 95.3 | 91.6 | 94.3 | 98.3 | 94.7 |
Chimpanzee | 95.3 | 92.2 | 94.3 | 98.3 | 94.8 |
Bovine CAPN2 | 77.0 | 65.7 | 59.9 | 51.7 | 62.5 |
QMEAN6 score | Inactive template structure (1QXP:B) | Inactive bovine CAPN1 structural model | Activated template structure (1KXR:B) | Activated bovine CAPN1 structural model | CAST4 bound to CAPN2 of template structure (3BOW) | CAST4 bound to CAPN1 structural model | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Raw score | Z-score | Raw score | Z-score | Raw score | Z-score | Raw score | Z-score | Raw score | Z-score | Raw score | Z-score | |
C-beta interaction energy | −170.90 | −0.82 | −124.35 | −1.00 | −73.49 | −1.20 | −160.43 | −0.63 | −314.42 | −0.01 | −213.98 | −0.30 |
All-atom pairwise energy | −16,945.12 | −0.41 | −14,017.57 | −0.85 | −7440.68 | −0.89 | −17,049.35 | −0.18 | −30,398.27 | 0.40 | −19,083.34 | −0.46 |
Solvation energy | −31.92 | −1.62 | −27.92 | −1.65 | −11.59 | −2.08 | −36.17 | −1.21 | −110.00 | 0.60 | −52.80 | −1.30 |
Torsion angle energy | −69.46 | −2.81 | −79.90 | −2.55 | −111.55 | 1.03 | −179.04 | −0.24 | −230.02 | −0.34 | −190.68 | −0.27 |
Secondary structure agreement | 78.2% | −0.12 | 80.2% | 0.28 | 74.8% | −1.40 | 80.5% | 0.35 | 80.4% | −0.19 | 78.1% | −0.76 |
Solvent accessibility agreement | 74.7% | −1.16 | 74.9% | −1.13 | 89.4% | 1.64 | 78.2% | −0.54 | 76.6% | −0.58 | 75.9% | −0.88 |
QMEAN6 score | 0.592 | −1.90 | 0.606 | −1.74 | 0.915 | 1.58 | 0.724 | −0.43 | 0.678 | −0.82 | 0.673 | −1.04 |
Residues | 788 | 703 | 321 | 683 | 914 | 742 | ||||||
PDFs total energy | - | 5790.3301 | - | 1348.0272 | - | 108,223 | ||||||
DOPE score | - | −74,339.4609 | - | −80,511.2891 | - | −86,723.3 |
PDB ID | Molecular description | The Ca2+ binding site | The residue conservation pattern * |
---|---|---|---|
1KXR | Ca2+ bound protease core of CAPN1(rat) | Site 1: Val99, Gly101, Asp106, Glu185 Site 2: Glu302, Asp309, Met 329, Asp331, Glu333 | Site 1: VGDE Site 2: EDMDE Site 3: ADEE |
1ZCM | CAPN1 protease core inhibited by ZLLYCH2F(human) | Site 1: Val99, Gly101, Asp106, Glu185 Site 2: Glu302, ASP309, Met329, Asp331, Glu333 | |
Activated CAPN1 structure model (bovine) | Site 1: Val99, Asp100, Gly101, Thr103, Asp106, Glu185 Site 2: Glu302, ASP309, Met329, Asp331, Glu333 Site 3: Ala557, Asp560, Glu562, Glu567 | ||
3BOW | Complex of CAPN2 and CAST(rat) | Site 1: Ile89, Gly90, Gly91, Asp96, Glu175 Site2: Glu292, Asp299, Gln319, Asp321, Glu323 Site3: Ala542, Asp545, Glu547, Glu552 Site 4: Asp585, Asp587, Ser589, Lys591, Glu596 Site 5: Asp615, Asp617, Ser618, Thr621, Glu626 Site 6: Asp658, Asn661 | Site 1: IGGDE Site 2: EDQDE Site 3: ADEE Site 4: DDSLE Site 5:DDRTE Site 6:DDDN |
3DF0 | Complex of CAPN2 and CAST(rat) | Site 1: Ile89, Gly90, Gly91, Asp96, Glu175 Site2: Glu292, Asp299, Gln319, Asp321, Glu323 Site 3: Ala542, Asp545, Ala546, Glu547, Glu552 Site 4: Glu547, Asp585, Asp587, Ser589, Lys591, Glu596 Site 5: Asp615, Asp617, Ser618, Thr621, Glu626 Site 6: Asp570, Asp658, Asp660, Asn661 |
PDB ID | Molecular description | Experimental details | Length | Sequence identity (%) | Sequence similarity (%) | E-value | Template |
---|---|---|---|---|---|---|---|
1QXP:B | Like CAPN1 (rat) | X-ray Diffraction (2.80 Å) | 788 | 74.6 | 82.4 | 0.0 | T |
1KXR:B | Ca2+ bound protease core of CAPN1 (rat) | X-ray Diffraction (2.07 Å) | 321 | 80.2 | 85.8 | 1 × 10−17 | T |
3BOW:A | CAPN2 catalytic subunit (rat) | X-ray Diffraction (2.40 Å) | 680 | 59.4 | 77 | 0.0 | T |
3BOW:C | CAST 4 domain (rat) | X-ray Diffraction (2.40 Å) | 65 | 72.9 | 86.4 | 3 × 10−10 | T |
1KFX:L | Form I of CAPN2 (human) | X-ray Diffraction (3.15 Å) | 640 | 57.1 | 75.7 | 0.0 | - |
1KFU:L | Form II of CAPN2 (human) | X-ray Diffraction (2.50 Å) | 699 | 61.4 | 81.3 | 0.0 | - |
3DF0:A | CAPN2 catalytic subunit (rat) | X-ray Diffraction (2.95 Å) | 676 | 59.5 | 77.5 | 0.0 | - |
1U5I:A | CAPN2 mutant Lys10Thr (rat) | X-ray Diffraction (2.86 Å) | 625 | 56.1 | 73.4 | 0.0 | - |
The regulation system | Interaction regions | Calpain residues * |
---|---|---|
The catalytic subunit of CAPN1/subdomains AB of CAST4 complex from both bovines (model structure) | CAPN1 and CAST4 subdomain B | Leu73, Ser78, Lys79, Ile83, Cys108, Gln109, Gly110, Ala111, Leu112, Gly113, Cys115, Trp116, Lys171, Lys174, Leu175, Val176, His179, Ser209, Thr210, Glu212, Ser251, Asp253, Ile254, Ser255, Ser256, Asp259, Met260, Ala262, Val263, Val269, Lys270, Gly271, His272, Ala273, Trp298, Glu300, Arg347, Glu349, Cys384, Arg385, Asn386, Pro388, Trp392, Asp439, Met440, Thr442, Tyr448, Lys463, Asp465, Phe467, Leu468, Ser469, Asn470, Ala471, Ser472, Arg475, Gln478, Phe479, Ile480, Asn481, Leu482, Arg483, Phe503 |
CAPN1 and CAST4 subdomain A | Asn548, Leu552, Gln555, Leu556, Ile571, Arg574, Ile575, Lys578, His579, Asp581, Phe612, Trp616, Ile619, Arg620, Leu623, Arg627, Asp630, Leu631, Lys633, Gly635 | |
The overall CAPN2/CAST4 complex from both rats (PDB ID: 3BOW) | CAP2 and CAST4 subdomain B | Leu63, Gly100, Ala101, Leu102, Lys161, Leu169, Gly198, Ile244, Thr245, Asp249, Gly261, His262, Ala263, Trp288, Arg375, Asn376, Leu454, Thr455, Arg457, Ala458, Arg461, Phe465, Asn467, Phe489 |
CAP2 and CAST4 subdomain A | Leu537, Gln540, Leu541, Ile556, Val560, Arg564, Trp601, Gln605, Gln608, Arg612, Asp615 | |
CAP2 and CAST4 subdomain C | Leu106, Leu110, Ile125, Val129, Arg132, His133, Trp170 |
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Chai, H.-H.; Lim, D.; Lee, S.-H.; Chai, H.-Y.; Jung, E. Homology Modeling Study of Bovine μ-Calpain Inhibitor-Binding Domains. Int. J. Mol. Sci. 2014, 15, 7897-7938. https://doi.org/10.3390/ijms15057897
Chai H-H, Lim D, Lee S-H, Chai H-Y, Jung E. Homology Modeling Study of Bovine μ-Calpain Inhibitor-Binding Domains. International Journal of Molecular Sciences. 2014; 15(5):7897-7938. https://doi.org/10.3390/ijms15057897
Chicago/Turabian StyleChai, Han-Ha, Dajeong Lim, Seung-Hwan Lee, Hee-Yeoul Chai, and Eunkyoung Jung. 2014. "Homology Modeling Study of Bovine μ-Calpain Inhibitor-Binding Domains" International Journal of Molecular Sciences 15, no. 5: 7897-7938. https://doi.org/10.3390/ijms15057897