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Strand 6B deformation and residues exposure towards N-terminal end of helix B during proteinase inhibition by Serpins.

Singh P, Jairajpuri MA - Bioinformation (2011)

Bottom Line: Helix B region in serpins is with several point mutations which result in pathological conditions due to polymerization.A cleaved polymer like conformation of antitrypsin also showed deformation of s6B and helix B exposure.These data for the first time show the importance of strand 6B deformation and exposure of helix B in smooth insertion of the reactive center loop during serpin inhibition and indicate that helix B exposure due to variants may increase its polymer propensity. serpin -serine protease inhibitors RCL -reactive center loop ASA -accessible surface area.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, Jamia Millia Islamia University, Jamia Nagar, New Delhi-110025, India; Mohamad Aman Jairajpuri- ;

ABSTRACT

Unlabelled: Serine Protease inhibitors (Serpins) like antithrombin, antitrypsin, neuroserpin, antichymotrypsin, protein C-inhibitor and plasminogen activator inhibitor is involved in important biological functions like blood coagulation, fibrinolysis, inflammation, cell migration and complement activation. Serpins native state is metastable, which undergoes transformation to a more stable state during the process of protease inhibition. Serpins are prone to conformation defects, however little is known about the factors and mechanisms which promote its conformational change and misfolding. Helix B region in serpins is with several point mutations which result in pathological conditions due to polymerization. Helix B analysis for residue burial and cavity was undertaken to understand its role in serpin structure function. A structural overlap and an accessible surface area analysis showed the deformation of strand 6B and exposure of helix B at N-terminal end in cleaved conformation but not in the native and latent conformation of various inhibitory serpins. A cleaved polymer like conformation of antitrypsin also showed deformation of s6B and helix B exposure. Cavity analysis showed that helix B residues were part of the largest cavity in most of the serpins in the native state which increase in size during the transformation to cleaved and latent states. These data for the first time show the importance of strand 6B deformation and exposure of helix B in smooth insertion of the reactive center loop during serpin inhibition and indicate that helix B exposure due to variants may increase its polymer propensity.

Abbreviations: serpin -serine protease inhibitors RCL -reactive center loop ASA -accessible surface area.

No MeSH data available.


Related in: MedlinePlus

Structural overlap of the native and cleaved conformation of strand 6B and helix B in serpins: Illustrations show the overlap of cleaved and native conformations in α1-antitrypsin, neuroserpin, protein C inhibitor and antichymotrypsin indicating the deformation of strand 6B. The analysis was performed using the PDB structure coordinates as follows A) antitrypsin [2Å native:pdb.1QLP(A), 2.6Å cleaved:1pdb.EZX(A)], B) neuroserpin [2.08Å native:pdb.3FGQ(A) and 1.79Å cleaved:pdb.3FO2(A) from human], C) protein C Inhibitor [2.30Å native: pdb.2HI9(A) and 2.40Å cleaved:pdb.1LQ8(A) from human] and D) antichymotrypsin [2.26Å native like delta conformation: pdb.1QMN(A) and 2.9Å cleaved :pdb.4CAA(A), antichymotrypsin from human]. Chimera software was used for creating the comparison and visualization.
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Figure 1: Structural overlap of the native and cleaved conformation of strand 6B and helix B in serpins: Illustrations show the overlap of cleaved and native conformations in α1-antitrypsin, neuroserpin, protein C inhibitor and antichymotrypsin indicating the deformation of strand 6B. The analysis was performed using the PDB structure coordinates as follows A) antitrypsin [2Å native:pdb.1QLP(A), 2.6Å cleaved:1pdb.EZX(A)], B) neuroserpin [2.08Å native:pdb.3FGQ(A) and 1.79Å cleaved:pdb.3FO2(A) from human], C) protein C Inhibitor [2.30Å native: pdb.2HI9(A) and 2.40Å cleaved:pdb.1LQ8(A) from human] and D) antichymotrypsin [2.26Å native like delta conformation: pdb.1QMN(A) and 2.9Å cleaved :pdb.4CAA(A), antichymotrypsin from human]. Chimera software was used for creating the comparison and visualization.

Mentions: Cleaved state of a serpin represents the inhibitory conformation where after cleavage reactive center loop inserts between strand 3A and strand 5A as strand 4A of β-sheet A. Structural overlap of strand 6B and helix B in thecleaved and native state of inhibitory serpins like antitrypsin, antichymotrypsin, neuroserpin and protein C inhibitor is shown in Figure 2. The comparison showed strand 6B was deformed in the cleaved state but not in the native state. In antitrypsin we see loss of one turn at the Cterminal end of the helix B in the cleaved structure (Figure 1) along with the deformation of the strand 6B. Antithrombin is a heparin binding anticoagulant inhibitor of factor Xa and thrombin that showed no deformation of strand 6B in the cleaved state (data not shown). Latent conformation of serpins is a loop inserted conformation without RCL cleavage, no strand 6B deformation was found in this state (data notshown).


Strand 6B deformation and residues exposure towards N-terminal end of helix B during proteinase inhibition by Serpins.

Singh P, Jairajpuri MA - Bioinformation (2011)

Structural overlap of the native and cleaved conformation of strand 6B and helix B in serpins: Illustrations show the overlap of cleaved and native conformations in α1-antitrypsin, neuroserpin, protein C inhibitor and antichymotrypsin indicating the deformation of strand 6B. The analysis was performed using the PDB structure coordinates as follows A) antitrypsin [2Å native:pdb.1QLP(A), 2.6Å cleaved:1pdb.EZX(A)], B) neuroserpin [2.08Å native:pdb.3FGQ(A) and 1.79Å cleaved:pdb.3FO2(A) from human], C) protein C Inhibitor [2.30Å native: pdb.2HI9(A) and 2.40Å cleaved:pdb.1LQ8(A) from human] and D) antichymotrypsin [2.26Å native like delta conformation: pdb.1QMN(A) and 2.9Å cleaved :pdb.4CAA(A), antichymotrypsin from human]. Chimera software was used for creating the comparison and visualization.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3046034&req=5

Figure 1: Structural overlap of the native and cleaved conformation of strand 6B and helix B in serpins: Illustrations show the overlap of cleaved and native conformations in α1-antitrypsin, neuroserpin, protein C inhibitor and antichymotrypsin indicating the deformation of strand 6B. The analysis was performed using the PDB structure coordinates as follows A) antitrypsin [2Å native:pdb.1QLP(A), 2.6Å cleaved:1pdb.EZX(A)], B) neuroserpin [2.08Å native:pdb.3FGQ(A) and 1.79Å cleaved:pdb.3FO2(A) from human], C) protein C Inhibitor [2.30Å native: pdb.2HI9(A) and 2.40Å cleaved:pdb.1LQ8(A) from human] and D) antichymotrypsin [2.26Å native like delta conformation: pdb.1QMN(A) and 2.9Å cleaved :pdb.4CAA(A), antichymotrypsin from human]. Chimera software was used for creating the comparison and visualization.
Mentions: Cleaved state of a serpin represents the inhibitory conformation where after cleavage reactive center loop inserts between strand 3A and strand 5A as strand 4A of β-sheet A. Structural overlap of strand 6B and helix B in thecleaved and native state of inhibitory serpins like antitrypsin, antichymotrypsin, neuroserpin and protein C inhibitor is shown in Figure 2. The comparison showed strand 6B was deformed in the cleaved state but not in the native state. In antitrypsin we see loss of one turn at the Cterminal end of the helix B in the cleaved structure (Figure 1) along with the deformation of the strand 6B. Antithrombin is a heparin binding anticoagulant inhibitor of factor Xa and thrombin that showed no deformation of strand 6B in the cleaved state (data not shown). Latent conformation of serpins is a loop inserted conformation without RCL cleavage, no strand 6B deformation was found in this state (data notshown).

Bottom Line: Helix B region in serpins is with several point mutations which result in pathological conditions due to polymerization.A cleaved polymer like conformation of antitrypsin also showed deformation of s6B and helix B exposure.These data for the first time show the importance of strand 6B deformation and exposure of helix B in smooth insertion of the reactive center loop during serpin inhibition and indicate that helix B exposure due to variants may increase its polymer propensity. serpin -serine protease inhibitors RCL -reactive center loop ASA -accessible surface area.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, Jamia Millia Islamia University, Jamia Nagar, New Delhi-110025, India; Mohamad Aman Jairajpuri- ;

ABSTRACT

Unlabelled: Serine Protease inhibitors (Serpins) like antithrombin, antitrypsin, neuroserpin, antichymotrypsin, protein C-inhibitor and plasminogen activator inhibitor is involved in important biological functions like blood coagulation, fibrinolysis, inflammation, cell migration and complement activation. Serpins native state is metastable, which undergoes transformation to a more stable state during the process of protease inhibition. Serpins are prone to conformation defects, however little is known about the factors and mechanisms which promote its conformational change and misfolding. Helix B region in serpins is with several point mutations which result in pathological conditions due to polymerization. Helix B analysis for residue burial and cavity was undertaken to understand its role in serpin structure function. A structural overlap and an accessible surface area analysis showed the deformation of strand 6B and exposure of helix B at N-terminal end in cleaved conformation but not in the native and latent conformation of various inhibitory serpins. A cleaved polymer like conformation of antitrypsin also showed deformation of s6B and helix B exposure. Cavity analysis showed that helix B residues were part of the largest cavity in most of the serpins in the native state which increase in size during the transformation to cleaved and latent states. These data for the first time show the importance of strand 6B deformation and exposure of helix B in smooth insertion of the reactive center loop during serpin inhibition and indicate that helix B exposure due to variants may increase its polymer propensity.

Abbreviations: serpin -serine protease inhibitors RCL -reactive center loop ASA -accessible surface area.

No MeSH data available.


Related in: MedlinePlus