Modeling the Structure of Yeast MATα1: An HMG-Box Motif with a C-Terminal Helical Extension

DOI: 10.4236/ojbiphy.2013.31001   PDF   HTML   XML   2,814 Downloads   5,988 Views   Citations


The yeast MATα1 is required for the activation of α-specific genes in Saccharomyces cerevisiae and thus confers the α-cell identity of the yeast. MATα1 contains a domain called the α-domain which has significant sequence identity to the HMG-box family of proteins. A multiple sequence alignment of several α-domains and various structurally determined HMG-box domains has revealed that both domains possess very similar structural and functional residues. We found that the basic amino acids of the N-terminal loop, the intercalating hydrophobic residues of the first helix, and the hydrophobic residues required for interactions within the core of the protein are remarkably conserved in α-domains and HMG-box proteins. Our generated molecular models suggest that the first and third helix will be shorter and that the HMG-box core is not an isolated domain. The region beyond the conserved HMG-box motif contains an extended helical region for about 20 - 30 amino acids. Structural models generated by comparative modeling and ab initio modeling reveal that this region will add two or more additional α-helices and will make significant contacts to helix III, II and I of the HMG-box core. We were able to illustrate how the extended α-domain would bind to DNA by merging of the α-domain and the LEF-1/DNA complex. The models we are reporting will be helpful in understanding how MATα1 binds to DNA with its partner MCM1 and activates transcription of α-specific genes. These models will also aid in future biophysical studies of MATα1 including the crystallization and structure determination.

Share and Cite:

D. Jackson, T. Lawson, R. Villafane and L. Gary, "Modeling the Structure of Yeast MATα1: An HMG-Box Motif with a C-Terminal Helical Extension," Open Journal of Biophysics, Vol. 3 No. 1, 2013, pp. 1-12. doi: 10.4236/ojbiphy.2013.31001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] L. A. Casselton, “Fungal Sex Genes—Searching for the Ancestors,” BioEssays, Vol. 30, No. 8, 2008, pp. 711-714. doi:10.1002/bies.20782
[2] G. F. Sprague, J. Rine and I. Herskowitz, “Control of Yeast Cell Type by the Mating-Type Locus: II. Genetic Interactions between MATα and Unlinked α-Specific STE Genes,” Journal of Molecular Biology, Vol. 153, No. 2, 1981, pp. 323-335. doi:10.1016/0022-2836(81)9.0281-3
[3] S. Lee, N. Corradi, S. Doan, F. S. Dietrich, P. J. Keeling and P. J. Keeling, “Evolution of the Sex-Related Locus and Genomic Features Shared in Microsporidia and Fungi,” PLos One 5, 2010, Article ID: 10539. doi:10.1371/journal.pone.0010539
[4] G. F. Sprague, Jr, L. C. Blair and J. Thorner, “Cell Interactions and the Regulation of Cell Type in Yeast Saccharomyces cerevisiae,” Annual Review of Microbiology, Vol. 37, 1983, pp. 623-660. doi:10.1146/annurev.mi.37.100183.003203
[5] D. R. Scannell, G. Butler and K. H. Wolfe, “Yeast Genome Evolution: The Origin of the Species,” Yeast, Vol. 24, No. 11, 2007, pp. 929-942.
[6] T. Koestler and I. Ebersberger, “Zygomycetes, Microsporidia, and the Evolutionary Ancestry of Sex Determination,” Genome Biology and Evolution, Vol. 3, 2011, pp. 186-194. doi:10.1093/gbe/evr009
[7] D. C. Hagan, L. Bruhn, C. Westby and G. F. Sprague, “Transcription of α-Specific Genes in Saccharomyces cerevisiae: DNA Sequence Requirements for Activity of the Coregulator Alpha1,” Molecular and Cellular Biology, Vol. 13, No. 11, 1993, pp. 6866-6875.
[8] P. Shore and A. Sharrocks, “The MADS-Box Family of Transcription Factors,” European Journal of Biochemistry, Vol. 229, 1995, pp. 1-13. doi:10.1111/j.1432-1033.1995.tb20430.x
[9] S. Tan and T. Richmond, “Crystal Structure of the Yeast MATα2/MCM1/DNA Ternary Complex,” Nature, Vol. 391, No. 6668, 1998, pp. 660-666. doi:10.1038/35563
[10] S. Tan, G. Ammerer and T. Richmond, “Interactions of Purified Transcription Factors: Binding of Yeast MATα1 and PRTF to Cell Type Specific, Upstream Activating Sequences,” EMBO Journal, Vol. 7, No. 13, 1988, pp. 4255-4264.
[11] E. Carr, J. Mead and A. Vershon, “α1-Induced DNA Bending Is Required for Transcriptional Activation by the MCM1-α1 Complex,” Nucleic Acid Research, Vol. 32, No. 8, 2004, pp. 2298-2305. doi:10.1093/nar/gkh560
[12] F. Lim, A. Hayes, A. West, A. Pic-Taylor, Z. Darieva, et al., “Mcm1p-Induced DNA Bending Regulates the Formation of Ternary Transcription Factor Complexes,” Molecular and Cellular Biology, Vol. 23, No. 2, 2003, pp. 450-461. doi:10.1128/MCB.23.2.450-461.2003
[13] T. Martin, S-W. Lu, H. Tilbeurgh, D. R. Ripoll, C. Dixelius, et al., “Tracing the Origin of the Fungal α1-Domain Places Its Ancestor in the HMG-Box Superfamily: Implication for Fungal Mating-Type Evolution,” PLos One 5: 2010, Article ID: e15199. doi:10.1371/journal.pone.0015199
[14] R. Reeves, “HMG Nuclear Proteins: Linking Chromatin Structure to Cellular Phenotype,” Biochim Biophys Acta, Vol. 1799, No. 1-2, 2010, p. 3.
[15] M. Stros, D. Launholt and K. Grasser, “The HMG-Box: A Versatile Protein Domain Occuring in a Wide Variety of DNA-Binding Proteins,” Cellular and Molecular Life Sciences, Vol. 64, No. 19-20, 2007, pp. 2590-2606. doi:10.1007/s00018-007-7162-3
[16] J. J. Love, X. Li, D. A. Case, K. Giese, R. Grosschedl and P. E. Wright, “Structural Basis for DNA Bending by the Architectural Transcription Factor LEF-1,” Nature, Vol. 376, No. 6543, 1995, pp. 791-795. doi:10.1038/376791a0
[17] H. Rhong, Y. Li, X. Shi, X. Zhang, Y. Gao, H. Dai, M. Teng, L. Niu, Q. Liu and Q. Hao, “Structure of Human Upstream Binding Factor HMG-Box 5 and Site for Binding of the Cell-Cycle Regulatory Factor TAF1,” Acta Crystallography Section D, Vol. D63, 2007, pp. 730-737. doi:10.1107/S0907444907017027
[18] F. V. Murphy 4th, R. M. Sweet and M. E. Churchill, “The Structure of a Chromosomal High Mobility Group Protein-DNA Complex Reveals Sequence-Neutral Mechanisms Important for Non-Sequence-Specific DNA Recognition,” EMBO Journal, Vol. 18, No. 23, 1999, pp. 6610-6618. doi:10.1093/emboj/18.23.6610
[19] U. M. Ohndorf, M. A. Rould, Q. He, C. O. Pabo and S. J. Lippard, “Basis for Recognition of Cisplatin-Modified DNA by High-Mobility-Group Proteins,” Nature, Vol. 399, No. 6737, 1999, pp. 708-712. doi:10.1038/21460
[20] H. M. Weir, P. J. Kraulis, C. S. Hill, A. R. Raine, E. D. Laue and J. O. Thomas, “Structure of the HMG-Box Motif in the B-Domain of HMG1,” EMBO Journal, Vol. 12, No. 4,1993, pp. 1311-1319.
[21] C. H. Hardman, R. W. Broad Hurst, A. R. Raine, K. D. Grasser, J. O. Thomas and E. D. Laue, “Structure of the A-Domain of HMG1 and Its Interaction with DNA as Studied by Heteronuclear Three and Four-Dimensional NMR Spectroscopy,” Biochemistry, Vol. 34, No. 51, 1995, pp. 16596-16607. doi:10.1021/bi00051a007
[22] A. Remenyi, K. Lins, L. J. Nissen and R. Reinbold, “Crystal Structure of the Pou/HMG/DNA Ternary Complex Suggests Differential Assembly of Oct4 and Sox2 on Two Enhancers,” Genes & Development, Vol. 17, No. 18, 2003, pp. 2048-2059.
[23] Y. Xu, W. Yang, J. Wu and Y. Shi, “Solution Structure of the First HMG-Box Domain in Human Upstream Binding Factor,” Biochemistry, Vol. 41, No. 17, 2002, pp. 5415-5420. doi:10.1021/bi015977a
[24] M. H. Werner, J. R. Huth, A. M. Gronenborn and G. M. Clore, “Molecular Basis of Human 46X,Y Sex Reversal Revealed from the Three-Dimensional Solution Structure of the Human SRY-DNA Complex,” Cell, Vol. 81, No. 5,1995, pp. 704-705.
[25] P. Palasingam, R. Jauch, C. K. L. Ng and P. R. Kolatkar, “The Structure of Sox17 Bound to DNA Reveals a Conserved Bending Topology but Selective Protein Interaction Platforms,” Journal of Molecular Biology, Vol. 388, No. 3, 2009, pp. 619-630.
[26] T. A. Gangelhoff, P. S. Mungalachetty, J. C. Nix and M. E. Churchill, “Structural Analysis and DNA Binding of the HMG Domains of the Human Mitochondrial Transcription Factor A,” Nucleic Acids Research, Vol. 37, No. 10, 2009, pp. 3153-3164. doi:10.1093/nar/gkp157
[27] K. Stott, G. S. Tang, K. B. Lee and J. O. Thomas, “Structure of Tandem HMG-Boxes and DNA,” Journal of Molecular Biology, Vol. 360, No. 1, 2006, pp. 90-104. doi:10.1016/j.jmb.2006.04.059
[28] D. C. Williams, M. Cai and G. M. Clore, “Molecular Basis for Synergistic Transcriptional Activation by Oct1 and Sox2 Revealed from the Solution Structure of the 42-kDa Oct1?Sox2?Hoxb1-DNA Ternary Transcription Factor Complex,” The Journal of Biological Chemistry, Vol. 279, No. 2, 2004, pp. 1449-1457. doi:10.1074/jbc.M309790200
[29] J. E. Masse, B. Wong, Y. -M. Yen, F. H.-T. Allain, R. C. Johnson and J. Feigon, “The S. cerevisiae Architectural HMGB Protein NHP6A Complexed with DNA: DNA and Protein Conformational Changes upon Binding,” Journal of Molecular Biology, Vol. 323, No. 2, 2002, pp. 263-284. doi:10.1016/S0022-2836(02)00938-5
[30] P. D. Cary, C. M. Read, B. Davis, P. C. Driscoll and C. Crane-Robinson, “Solution Structure and Backbone Dynamics of the DNA-Binding Domain of Mouse Sox-5,” Protein Science, Vol. 10, No. 1, 2001, pp. 83-98. doi:10.1110/ps.32801
[31] N. Kasai, Y. Tsunaka, I. Ohki, S. Hirose, K. Morikawa and S. Tate, “Solution Structure of the HMG-Box Domain in the SSRP1 Subunit of FACT,” Journal of Biomolecular NMR, Vol. 32, No. 1, 2005, pp. 83-88. doi:10.1007/s10858-005-3662-3
[32] C. Camacho, G. Coulouris, V. Avagyan N. Ma, J. Papadopoulos, et al., “BLAST+: Architecture and Applications,” BMC Bioinformatics, Vol. 10, 2008, p. 421. doi:10.1186/1471-2105-10-421
[33] S. Amarendran, J. W. Menkhoff, M. Kaufmann and B. Morgenstern, “DIALIGN-TX: An Improved Algorithm for Segment Based Multiple Sequence Alignment,” BMC Bioinformatics, Vol. 6, 2005, p. 66. doi:10.1186/1471-2105-6-66
[34] N. Guex and M. C. Peitsch, “SWISS-MODEL and the Swiss Pdb Viewer: An Environment for Comparative Protein Modeling,” Electrophoresis, Vol. 18, No. 15, 1997, pp. 2714-2723. doi:10.1002/elps.1150181505
[35] D. E. Kim, D. Chivian and D. Baker, “Protein Structure Prediction and Analysis Using the Robetta Server,” Nucleic Acids Research, Vol. 32, No. 2, 2004, pp. W526-W531. doi:10.1093/nar/gkh468
[36] S. Raman, R. Vernon, J. Thompson, M. Tyka, R. Sadreyev, J. Pei, D. Kim, E. Kellogg, F. DiMaio, O. Lange, L. Kinch, W. Sheffler, B. Kim, R. Das, N. V. Grishin and D. Baker, “Structure Prediction for CASP8 with All-Atom Refinement Using Rosetta,” Proteins: Structure, Function and Bioinformatics, Vol. 77, No. S9, 2009, pp. 89-99. doi:10.1002/prot.22540
[37] R. A. Laskowski, M. W. MacArthur, D. S. Moss and J. M. Thornton, “PROCHECK: A Program to Check the Stereochemical Quality of Protein Structures,” Journal of Applied Crystallography, Vol. 26, 1993, pp. 283-291. doi:10.1107/S0021889892009944
[38] C. Colovos and T. O. Yeates, “Verifications of Protein Structures: Patterns of Nonbonded Atomic Interactions.” Protein Science, Vol. 2, No. 9, 1993, pp. 1511-1519. doi:10.1002/pro.5560020916
[39] F. Melo, R. Sanchez and A. Sali, “Statistical Potentials for Fold Assessment,” Protein Science, Vol. 11, No. 2, 2002, pp. 430-448.
[40] D. Eramian, N. Eswar, M. Y. Shen and A. Sali, “How Well Can the Accuracy of Comparative Protein Structure Models Be Predicted?” Protein Science, Vol. 17, No. 11, 2008, pp. 1881-1893. doi:10.1110/ps.036061.108
[41] P. Benkert, S. C. E. Tosatto and D. Schomburg, “QMEAN: A Comprehensive Scoring Function for Model Quality Assessment,” Proteins: Structure, Function, and Bioinformatics, Vol. 71, No. 1, 2008, pp. 261-277. doi:10.1002/prot.21715
[42] P. Benkert, M. Biasini and T. Schwede, “Toward the Estimation of the Absolute Quality of Individual Protein Structure Models,” Bioinformatics, Vol. 27, No. 3, 2010, pp. 343-350. doi:10.1093/bioinformatics/btq662
[43] P. Benkert, M. Künzli and T. Schwede, “QMEAN Server for Protein Model Quality Estimation,” Nucleic Acids Research, Vol. 37, 2009, pp. 510-540. doi:10.1093/nar/gkp322
[44] E. Krissinel and K. Henrick, “Secondary-Structure Matching (SSM), a New Tool for Fast Protein Structure Alignment in Three Dimensions,” Acta Crystallographica Section D, Vol. 60, No.1, 2004, pp. 2256-2268. doi:10.1107/S0907444904026460
[45] L. J. Mcgruffin, K. Bryson and D. T. Jones, “The PSIPRED Protein Structure Prediction Server,” Bioinformatics, vol. 16, No. 4, 2000, pp. 404-405.
[46] J. D. Thompson, T. J. Gibson, F. Plewniak, F. Jeanmougin and D. G. Higgins, “The ClustalX Windows Interface: Flexible Strategies for Multiple Sequence Alignment Aided by Quality Analysis Tools,” Nucleic Acids Research, Vol. 24, 1997, pp. 4876-4882.
[47] A. M. Waterhouse, J. B. Procter, D. M. A. Martin, M. Clamp and G. J. Barton, “Jalview Version 2—A Multiple Sequence Alignment Editor and Analysis Workbench,” Bioinformatics, Vol. 25, No. 9, 2009, pp. 1189-1191. doi: 10.1093/bioinformatics/btp033
[48] R. C. Edgar, “MUSCLE, Multiple Sequence Alignment with High Accuracy and High Thoroughput,” Nucleic Acid Research, Vol. 32, No. 5, 2004, p. 1792.
[49] “The PyMOL Molecular Graphics System,” Version, Schrodinger, 2006.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.