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Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

Avram S, Milac A, Mernea M, Mihailescu D, Putz MV, Buiu C - Int J Mol Sci (2014)

Bottom Line: QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes.The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53-0.65) and fitted correlation r2 (0.82-0.90).Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. speranta.avram@gmail.com.

ABSTRACT
Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding to specific partners (cell-division cycle protein 20 (Cdc20) or Mad1) were targets of previous pharmacogenomics studies. Here, Mad2 binding to Cdc20 and the interconversion rate from open to closed Mad2 were predicted and the molecular features with a critical contribution to these processes were determined by extending the quantitative structure-activity relationship (QSAR) method to large-size proteins such as Mad2. QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes. The most relevant descriptors identified for predicting Mad2 native and mutants action mechanism and their involvement in genetic disorders are the steric (van der Waals area and solvent accessible area and their subdivided) and energetic van der Waals energy descriptors. The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53-0.65) and fitted correlation r2 (0.82-0.90). Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.

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Related in: MedlinePlus

Variation of molecular descriptors for most relevant mutants. (a) Mad2 structure (Protein Data Bank code: 1S2H [17]) in ribbon representation, molecular surface colored light gray and mutants side chains represented as sticks. Only side chains of most relevant mutants are displayed, to illustrate their position within the structure; and (b–d) Deviation of molecular descriptors calculated as the difference between values for native protein and mutants: Van der Waals energy (b), protein hydrophobic moment (c) and protein hydrophobic ASA (d). Order of mutants (thus also mutants labelling) is the same in all plots.
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ijms-15-21381-f002: Variation of molecular descriptors for most relevant mutants. (a) Mad2 structure (Protein Data Bank code: 1S2H [17]) in ribbon representation, molecular surface colored light gray and mutants side chains represented as sticks. Only side chains of most relevant mutants are displayed, to illustrate their position within the structure; and (b–d) Deviation of molecular descriptors calculated as the difference between values for native protein and mutants: Van der Waals energy (b), protein hydrophobic moment (c) and protein hydrophobic ASA (d). Order of mutants (thus also mutants labelling) is the same in all plots.

Mentions: Based on clinical and structural data [10,15] demonstrating that Mad2 C-terminal active domain is deeply involved in the interactions with specific partners (Mad1 and Cdc20) and undergoes major conformational changes to allow these interactions, we evaluated the molecular descriptors values of C-Mad2 native and mutants, including de novo mutants we developed. In our study, molecular descriptors belong to MOE 10 data base were calculated for C-terminal Mad2 native and mutants (residues 190–205) and evaluated for their significant fluctuations. For a better interpretation of the results in the light of the SAR study, we selected twelve Mad2 mutants which adopt both open and closed configurations and interact with Cdc20 (Figure 2a–d).


Structure-biological function relationship extended to mitotic arrest-deficient 2-like protein Mad2 native and mutants-new opportunity for genetic disorder control.

Avram S, Milac A, Mernea M, Mihailescu D, Putz MV, Buiu C - Int J Mol Sci (2014)

Variation of molecular descriptors for most relevant mutants. (a) Mad2 structure (Protein Data Bank code: 1S2H [17]) in ribbon representation, molecular surface colored light gray and mutants side chains represented as sticks. Only side chains of most relevant mutants are displayed, to illustrate their position within the structure; and (b–d) Deviation of molecular descriptors calculated as the difference between values for native protein and mutants: Van der Waals energy (b), protein hydrophobic moment (c) and protein hydrophobic ASA (d). Order of mutants (thus also mutants labelling) is the same in all plots.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264231&req=5

ijms-15-21381-f002: Variation of molecular descriptors for most relevant mutants. (a) Mad2 structure (Protein Data Bank code: 1S2H [17]) in ribbon representation, molecular surface colored light gray and mutants side chains represented as sticks. Only side chains of most relevant mutants are displayed, to illustrate their position within the structure; and (b–d) Deviation of molecular descriptors calculated as the difference between values for native protein and mutants: Van der Waals energy (b), protein hydrophobic moment (c) and protein hydrophobic ASA (d). Order of mutants (thus also mutants labelling) is the same in all plots.
Mentions: Based on clinical and structural data [10,15] demonstrating that Mad2 C-terminal active domain is deeply involved in the interactions with specific partners (Mad1 and Cdc20) and undergoes major conformational changes to allow these interactions, we evaluated the molecular descriptors values of C-Mad2 native and mutants, including de novo mutants we developed. In our study, molecular descriptors belong to MOE 10 data base were calculated for C-terminal Mad2 native and mutants (residues 190–205) and evaluated for their significant fluctuations. For a better interpretation of the results in the light of the SAR study, we selected twelve Mad2 mutants which adopt both open and closed configurations and interact with Cdc20 (Figure 2a–d).

Bottom Line: QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes.The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53-0.65) and fitted correlation r2 (0.82-0.90).Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91-95 Spl. Independentei, Bucharest 050095, Romania. speranta.avram@gmail.com.

ABSTRACT
Overexpression of mitotic arrest-deficient proteins Mad1 and Mad2, two components of spindle assembly checkpoint, is a risk factor for chromosomal instability (CIN) and a trigger of many genetic disorders. Mad2 transition from inactive open (O-Mad2) to active closed (C-Mad2) conformations or Mad2 binding to specific partners (cell-division cycle protein 20 (Cdc20) or Mad1) were targets of previous pharmacogenomics studies. Here, Mad2 binding to Cdc20 and the interconversion rate from open to closed Mad2 were predicted and the molecular features with a critical contribution to these processes were determined by extending the quantitative structure-activity relationship (QSAR) method to large-size proteins such as Mad2. QSAR models were built based on available published data on 23 Mad2 mutants inducing CIN-related functional changes. The most relevant descriptors identified for predicting Mad2 native and mutants action mechanism and their involvement in genetic disorders are the steric (van der Waals area and solvent accessible area and their subdivided) and energetic van der Waals energy descriptors. The reliability of our QSAR models is indicated by significant values of statistical coefficients: Cross-validated correlation q2 (0.53-0.65) and fitted correlation r2 (0.82-0.90). Moreover, based on established QSAR equations, we rationally design and analyze nine de novo Mad2 mutants as possible promoters of CIN.

Show MeSH
Related in: MedlinePlus