Matthew Hj Cordes

Matthew Hj Cordes

Associate Professor, Chemistry and Biochemistry-Sci
Associate Professor, BIO5 Institute
Primary Department
Contact
(520) 626-1175

Research Interest

Research Interest

Matthew Cordes, Ph.D. is an Associate Professor of Chemistry and Biochemistry at the University of Arizona College of Science. Dr. Cordes’ research focuses on the origin and evolution of new protein structures and functions. He has published approximately 30 original research papers and presents his work frequently at national meetings such as the Protein Society and Gordon Research Conferences on Proteins and Biopolymers. Dr. Cordes’ primary research contributions are in four fields of protein evolution. First, his laboratory has identified cases in which a new type of protein structure has evolved from a preexisting structure. Second, he has identified evolutionary codes by which proteins that bind specific sites on double-stranded DNA evolve to recognize new target sites. Third, he studies the evolution of proteins in bloodsucking insects and spiders that affect blood homeostasis or cause dermonecrotic effects in mammalian tissue. Finally, he uses bioinformatics to identify hidden patterns in protein sequences that allow them to fold correctly and avoid aggregation such as that which occurs in Alzheimer’s disease. Dr. Cordes presently holds a BIO5 pilot project seed grant to study the evolution of enzyme toxins in brown spider venom.

Publications

Eaton, K. V., Anderson, W. J., Dubrava, M. S., Kumirov, V. K., Dykstra, E. M., & Cordes, M. H. (2015). Studying protein fold evolution with hybrids of differently folded homologs. Protein engineering, design & selection : PEDS, 28(8), 241-50.

To study the sequence determinants governing protein fold evolution, we generated hybrid sequences from two homologous proteins with 40% identity but different folds: Pfl 6 Cro, which has a mixed α + β structure, and Xfaso 1 Cro, which has an all α-helical structure. First, we first examined eight chimeric hybrids in which the more structurally conserved N-terminal half of one protein was fused to the more structurally divergent C-terminal half of the other. None of these chimeras folded, as judged by circular dichroism spectra and thermal melts, suggesting that both halves have strong intrinsic preferences for the native global fold pattern, and/or that the interfaces between the halves are not readily interchangeable. Second, we examined 10 hybrids in which blocks of the structurally divergent C-terminal region were exchanged. These hybrids showed varying levels of thermal stability and suggested that the key residues in the Xfaso 1 C terminus specifying the all-α fold were concentrated near the end of helix 4 in Xfaso 1, which aligns to the end of strand 2 in Pfl 6. Finally, we generated hybrid substitutions for each individual residue in this critical region and measured thermal stabilities. The results suggested that R47 and V48 were the strongest factors that excluded formation of the α + β fold in the C-terminal region of Xfaso 1. In support of this idea, we found that the folding stability of one of the original eight chimeras could be rescued by back-substituting these two residues. Overall, the results show not only that the key factors for Cro fold specificity and evolution are global and multifarious, but also that some all-α Cro proteins have a C-terminal subdomain sequence within a few substitutions of switching to the α + β fold.

Bouvignies, G., Vallurupalli, P., Cordes, M. H., Hansen, D., & Kay, L. E. (2011). Measuring 1HN temperature coefficients in invisible protein states by relaxation dispersion NMR spectroscopy. Journal of Biomolecular NMR, 50(1), 13-18.

PMID: 21424227;PMCID: PMC3229278;Abstract:

A method based on the Carr-Purcell-Meiboom- Gill relaxation dispersion experiment is presented for measuring the temperature coefficients of amide proton chemical shifts of low populated 'invisible' protein states that exchange with a 'visible' ground state on the millisecond time-scale. The utility of the approach is demonstrated with an application to an I58D mutant of the Pfl6 Cro protein that undergoes exchange between the native, folded state and a cold denatured, unfolded conformational ensemble that is populated at a level of 6% at 2.5°C. A wide distribution of amide temperature coefficients is measured for the unfolded state. The distribution is centered about -5.6 ppb/K, consistent with an absence of intra-molecular hydrogen bonds, on average. However, the large range of values (standard deviation of 2.1 ppb/K) strongly supports the notion that the unfolded state of the protein is not a true random coil polypeptide chain. © Springer Science+Business Media B.V. 2011.

H., M., & Berson, J. A. (1996). Medium effects on the rates of stereomutation of a pair of diastereomeric cyclopropanones. Ground state stabilization in nucleophilic solvents induces deviation from solvent polarity controlled behavior. Journal of the American Chemical Society, 118(26), 6241-6251.

Abstract:

The synthesis of the two stereoisomers of spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropan)-2'-one, 3a and 4a, from diazomethane and the ketene 2-carbonylylbicyclo[2.2.1]heptane in ether at 195 K yields a ~1.6 to 1 ratio. At 245 K, the ratio changes in a first-order manner, with an observed rate constant of 1.7 x 10-4 s-1, to an equilibrium ratio of 0.8 to 1. The temperature dependence of the interconversion of 3a and 4a (GC method) and that of their dideuterio derivatives 3b and 4b (NMR method) have been determined and yield activation parameters E(a) = 16.3 ± 1.4 kcal/mol and log A = 10.4 ± 1.4 (A in s-1) (GC method) and E(a) = 15.3 ± 1.4 and log A = 9.6 ± 1.4 (NMR method). The free energies of activation at 239 K have been determined in four solvents: dichloromethane (16.1 kcal/mol), acetone (17.7), hexane (17.9), and ether (19.1). The solvent dependence does not correlate well with commonly used measures of solvent polarity, and the reaction is unexpectedly slow in acetone and ether. This deceleration is explained in terms of nucleophilic association of these solvents with the carbonyl groups in the cyclopropanones, leading to a ground state stabilization.

Degnan, P. H., Michalowski, C. B., Babić, A. C., Cordes, M. H., & Little, J. W. (2007). Conservation and diversity in the immunity regions of wild phages with the immunity specificity of phage λ. Molecular Microbiology, 64(1), 232-244.

PMID: 17376085;Abstract:

The gene regulatory circuitry of phage λ is among the best-understood circuits. Much of the circuitry centres around the immunity region, which includes genes for two repressors, CI and Cro, and their cis-acting sites. Related phages, termed lambdoid phages, have different immunity regions, but similar regulatory circuitry and genome organization to that of λ, and show a mosaic organization, arising by recombination between lambdoid phages. We sequenced the immunity regions of several wild phages with the immunity specificity of λ, both to determine whether natural variation exists in regulation, and to analyse conservation and variability in a region rich in well-studied regulatory elements. CI, Cro and their cis-acting sites are almost identical to those in λ, implying that regulatory mechanisms controlled by the immunity region are conserved. A segment adjacent to one of the operator regions is also conserved, and may be a novel regulatory element. In most isolates, different alleles of two regulatory proteins (N and CII) flank the immunity region; possibly the lysis-lysogeny decision is more variable among isolates. Extensive mosaicism was observed for several elements flanking the immunity region. Very short sequence elements or microhomologies were also identified. Our findings suggest mechanisms by which fine-scale mosaicism arises. © 2007 The Authors.

Hall, B. M., Roberts, S. A., Heroux, A. M., & Cordes, M. H. (2008). Two structures of a lambda Cro variant highlight dimer flexibility but disfavor major dimer distortions upon specific binding of cognate DNA. Journal of Molecular Biology, 375(3).

Previously reported crystal structures of free and DNA-bound dimers of lambda Cro differ strongly (about 4 A backbone rmsd), suggesting both flexibility of the dimer interface and induced-fit protein structure changes caused by sequence-specific DNA binding. Here, we present two crystal structures, in space groups P3(2)21 and C2 at 1.35 and 1.40 A resolution, respectively, of a variant of lambda Cro with three mutations in its recognition helix (Q27P/A29S/K32Q, or PSQ for short). One dimer structure (P3(2)21; PSQ form 1) resembles the DNA-bound wild-type Cro dimer (1.0 A backbone rmsd), while the other (C2; PSQ form 2) resembles neither unbound (3.6 A) nor bound (2.4 A) wild-type Cro. Both PSQ form 2 and unbound wild-type dimer crystals have a similar interdimer beta-sheet interaction between the beta1 strands at the edges of the dimer. In the former, an infinite, open beta-structure along one crystal axis results, while in the latter, a closed tetrameric barrel is formed. Neither the DNA-bound wild-type structure nor PSQ form 1 contains these interdimer interactions. We propose that beta-sheet superstructures resulting from crystal contact interactions distort Cro dimers from their preferred solution conformation, which actually resembles the DNA-bound structure. These results highlight the remarkable flexibility of lambda Cro but also suggest that sequence-specific DNA binding may not induce large changes in the protein structure.