Martin Horvath
Associate Professor of Biology
B.S. Brown University
Ph.D. University of Chicago
Martin Horvath's Lab Page
Martin Horvath's PubMed Literature Search
Research
Telomeres are the physical termini of linear chromosomes in eukaryotes. At the very end, proteins that recognize and bind single-stranded DNA have evolved specialized roles to prevent this DNA from eliciting inappropriate DNA repair and recombination, events that would otherwise destabilize the genome. Additionally, these telomere end-binding proteins regulate access to telomerase, acting as repressors during quiescent phases and as processivity factors timed with DNA synthesis during S-phase. My work is focused on understanding the molecular physiology of telomere ends derived from single-celled eukaryotes. We use x-ray crystallography complemented by other solution-phase biophysical methods to answer questions related to telomere protein function and evolution, including how molecular interactions establish sequence-specificity recognition and how allostery regulates telomere complex assembly and disassembly. Since changes in telomere structure are tied to apoptosis and proliferation, answers to such questions will help us understand the basic molecular mechanisms underlying aging and cancer.
(a) Complex of telomere protein and single-stranded DNA from Sterkiella nova. Sketch is adapted from a 1.85 Å resolution co-crystal structure. The principle DNA-binding activity resides in the telomere end-binding protein (TEBP)-alpha subunit (striped, N-term domain). TEBP-beta (solid) associates by means of an extended segment (IDPR1) that contacts the beta-binding domain of TEBP-alpha (speckled).
(b) 2D NMR signals indicate that residues in IDPR1 lack intrinsic structure in the dissociated form. IDPR1 and IDPR2 are thought to be trigger points for allosteric regulation of telomere end structure and function, a hypothesis that remains untested.
References
1. O’Shea VL, Cao S, Richards JL, Horvath MP, David SS (2009) Structural illumination of a MutY glycosylase reaction coordinate intermediate. In Preparation
2. Zakharova E, Horvath MP, Goldenberg D (2009) Structure of a serine protease poised to resynthesize a peptide bond. Proc Natl Acad Sci USA, In Press
3. Horvath MP (2008) Single-stranded nucleic acid-binding proteins, in Protein-Nucleic Acid Interactions: Structural Biology (Rice PA, Correll CC, Eds.), pp 91-128, Royal Society of Chemistry, London
4. Horvath MP (2008) Evolution of telomere binding proteins, in Origin and Evolution of Telomeres (Tomaska L, Nosek J, Eds.), pp 83-99, Landes Bioscience, Austin, TX
5. Suzuki T, McKenzie M, Ott E, Ilkun O, Horvath MP (2006) DNA binding affinity and sequence permutation preference of the telomere protein from Euplotes crassus. Biochemistry 45:8628-38
6. Dy CY, Buczek P, Imperial JS, Bulaj G, Horvath MP (2006) Structure of conkunitzin-S1, a neurotoxin and Kunitz-fold disulfide variant from cone snail. Acta Crystallogr D Biol Crystallogr 62:980-90
7. Buczek P, Horvath MP (2006) Structural reorganization and the cooperative binding of single-stranded telomere DNA in Sterkiella nova. J Biol Chem 281:40124-34
8. Buczek P, Horvath MP (2006) Thermodynamic characterization of binding Oxytricha nova single strand telomere DNA with the alpha protein N-terminal domain. J Mol Biol 359:1217-34
9. Buczek P, Orr RS, Pyper SR, Shum M, Kimmel E, Ota I, Gerum SE, Horvath MP (2005) Binding linkage in a telomere DNA-protein complex at the ends of Oxytricha nova chromosomes. J Mol Biol 350:938-52
10. Horvath MP, Schultz SC (2001) DNA G-quartets in a 1.86 A resolution structure of an Oxytricha nova telomeric protein-DNA complex. J Mol Biol 310:367-77
11. Horvath MP, Schweiker VL, Bevilacqua JM, Ruggles JA, Schultz SC (1998) Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA. Cell 95:963-74
