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

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

Journal Name: Current Proteomics

Volume 14 , Issue 4 , 2017

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Graphical 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.

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Article Details

Year: 2017
Published on: 16 November, 2017
Page: [254 - 260]
Pages: 7
DOI: 10.2174/1570164614666170607120923
Price: $25

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