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

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

Volume: 14 Issue: 4

Author(s): Speranta Avram, Iulia Alexandrescu, Alin Puia, Ana Maria Udrea, Maria Mernea, Dan Florin Mihailescu and Livia-Cristina Borcan*

Affiliation:

• Department of Occupational Health, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timisoara-300041,Romania

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

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

Cite this article as:

Avram Speranta , Alexandrescu Iulia , Puia Alin , Udrea Maria Ana , Mernea Maria , Mihailescu Florin Dan and Borcan Livia-Cristina*, Aneuploidy-Inducing Mutations in Mitotic Checkpoint Protein hMad1-Carboxi Terminal Domain Analyzed by SAR and Computational Mutagenesis, Current Proteomics 2017; 14 (4) . https://dx.doi.org/10.2174/1570164614666170607120923