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Aneuploidy-Inducing Mutations in Mitotic Checkpoint Protein hMad1-Carboxi Terminal Domain Analyzed by SAR and Computational Mutagenesis

[ Vol. 14 , Issue. 4 ]

Author(s):

Speranta Avram, Iulia Alexandrescu, Alin Puia, Ana Maria Udrea, Maria Mernea, Dan Florin Mihailescu and Livia-Cristina Borcan*   Pages 254 - 260 ( 7 )

Abstract:


Background: At the cellular level, normal chromosome segregation is ensured by the intrinsic mechanics of mitosis and the proper functioning of the error-checking spindle assembly checkpoint (SAC). Protein Mad1 (the mitotic arrest-deficient), an important SAC component, plays a crucial role in avoiding cellular aneupoidy, a state leading to genetic diseases such as cancer or bipolar disorder.

Objective: To clarify the role of aneuploidy in genetic diseases, a number of wild type (wt) and mutant spindle checkpoint proteins have been studied, but till now the process is not well understood.

Method: Here, we report a number of 32 Mad1 mutants (8 already known to induce aneuploidy or Mad1 dimer destabilization and 24 de novo mutants designed by us) comprising mutation in the carboxi-terminal domain (CTD) represented by residues 598-718. Their molecular features (electronic, steric, and also the descriptors derived directly from amino acids sequence: counts of atom and bound types, dihedral angles) were calculated and compared by structure-activity relationships methods (SAR) in order to elucidate their possible contribution to aneuploidy.

Results: Our results suggest that some molecular descriptors of Mad1-CTD mutants and wt Mad1, like accessible solvent surface areas and its derivatives, could be important for predicting aneuploidy induced by Mad1 improper function.

Conclusion: It was found that molecular descriptors of Mad1 wt and mutants evaluated here are important resources for upcoming computational studies focused on aneuploidy, provided kinetic data about Mad1- kinetocore and/or Mad1-Bub1 interactions

Keywords:

Aneuploidy, computational mutagenesis, genetic disorder, Mad1 mutants, SAR, molecular descriptors.

Affiliation:

Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Department of Occupational Health, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara-300041

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