Person: Green, Anna
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Green
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Anna
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Green, Anna
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Publication Sequence co-evolution gives 3D contacts and structures of protein complexes(eLife Sciences Publications, Ltd, 2014) Hopf, Thomas A; Schärfe, Charlotta P I; Rodrigues, João P G L M; Green, Anna; Kohlbacher, Oliver; Sander, Chris; Bonvin, Alexandre M J J; Marks, DeboraProtein–protein interactions are fundamental to many biological processes. Experimental screens have identified tens of thousands of interactions, and structural biology has provided detailed functional insight for select 3D protein complexes. An alternative rich source of information about protein interactions is the evolutionary sequence record. Building on earlier work, we show that analysis of correlated evolutionary sequence changes across proteins identifies residues that are close in space with sufficient accuracy to determine the three-dimensional structure of the protein complexes. We evaluate prediction performance in blinded tests on 76 complexes of known 3D structure, predict protein–protein contacts in 32 complexes of unknown structure, and demonstrate how evolutionary couplings can be used to distinguish between interacting and non-interacting protein pairs in a large complex. With the current growth of sequences, we expect that the method can be generalized to genome-wide elucidation of protein–protein interaction networks and used for interaction predictions at residue resolution. DOI: http://dx.doi.org/10.7554/eLife.03430.001Publication Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4(eLife Sciences Publications, Ltd, 2016) Nicoludis, John M.; Vogt, Bennett; Green, Anna; Schärfe, Charlotta PI; Marks, Debora; Gaudet, RachelleProtocadherins (Pcdhs) are cell adhesion and signaling proteins used by neurons to develop and maintain neuronal networks, relying on trans homophilic interactions between their extracellular cadherin (EC) repeat domains. We present the structure of the antiparallel EC1-4 homodimer of human PcdhγB3, a member of the γ subfamily of clustered Pcdhs. Structure and sequence comparisons of α, β, and γ clustered Pcdh isoforms illustrate that subfamilies encode specificity in distinct ways through diversification of loop region structure and composition in EC2 and EC3, which contains isoform-specific conservation of primarily polar residues. In contrast, the EC1/EC4 interface comprises hydrophobic interactions that provide non-selective dimerization affinity. Using sequence coevolution analysis, we found evidence for a similar antiparallel EC1-4 interaction in non-clustered Pcdh families. We thus deduce that the EC1-4 antiparallel homodimer is a general interaction strategy that evolved before the divergence of these distinct protocadherin families. DOI: http://dx.doi.org/10.7554/eLife.18449.001Publication Core Genes Evolve Rapidly in the Long-Term Evolution Experiment with Escherichia coli(Oxford University Press, 2017) Maddamsetti, Rohan; Hatcher, Philip J.; Green, Anna; Williams, Barry L.; Marks, Debora; Lenski, Richard E.Bacteria can evolve rapidly under positive selection owing to their vast numbers, allowing their genes to diversify by adapting to different environments. We asked whether the same genes that evolve rapidly in the long-term evolution experiment (LTEE) with Escherichia coli have also diversified extensively in nature. To make this comparison, we identified ∼2000 core genes shared among 60 E. coli strains. During the LTEE, core genes accumulated significantly more nonsynonymous mutations than flexible (i.e., noncore) genes. Furthermore, core genes under positive selection in the LTEE are more conserved in nature than the average core gene. In some cases, adaptive mutations appear to modify protein functions, rather than merely knocking them out. The LTEE conditions are novel for E. coli, at least in relation to its evolutionary history in nature. The constancy and simplicity of the environment likely favor the complete loss of some unused functions and the fine-tuning of others.Publication Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000–2013(Oxford University Press, 2016) Grad, Yonatan; Harris, Simon R.; Kirkcaldy, Robert D.; Green, Anna; Marks, Debora; Bentley, Stephen D.; Trees, David; Lipsitch, MarcBackground. Treatment of Neisseria gonorrhoeae infection is empirical and based on population-wide susceptibilities. Increasing antimicrobial resistance underscores the potential importance of rapid diagnostic tests, including sequence-based tests, to guide therapy. However, the usefulness of sequence-based diagnostic tests depends on the prevalence and dynamics of the resistance mechanisms. Methods. We define the prevalence and dynamics of resistance markers to extended-spectrum cephalosporins, macrolides, and fluoroquinolones in 1102 resistant and susceptible clinical N. gonorrhoeae isolates collected from 2000 to 2013 via the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project. Results. Reduced extended-spectrum cephalosporin susceptibility is predominantly clonal and associated with the mosaic penA XXXIV allele and derivatives (sensitivity 98% for cefixime and 91% for ceftriaxone), but alternative resistance mechanisms have sporadically emerged. Reduced azithromycin susceptibility has arisen through multiple mechanisms and shows limited clonal spread; the basis for resistance in 36% of isolates with reduced azithromycin susceptibility is unclear. Quinolone-resistant N. gonorrhoeae has arisen multiple times, with extensive clonal spread. Conclusions. Quinolone-resistant N. gonorrhoeae and reduced cefixime susceptibility appear amenable to development of sequence-based diagnostic tests, whereas the undefined mechanisms of resistance to ceftriaxone and azithromycin underscore the importance of phenotypic surveillance. The identification of multidrug-resistant isolates highlights the need for additional measures to respond to the threat of untreatable gonorrhea.Publication Coevolution of interacting proteins through non-contacting and non-specific mutations(Cold Spring Harbor Laboratory, 2021-10-08) Ding, Fengning; Green, Anna; Wang, Boyuan; Lite, Thuy-Lan; Weinstein, Eli; Marks, Debora; Laub, Michael T.SummaryProteins often accumulate neutral mutations that do not affect current functions1 but can profoundly influence future mutational possibilities and functions2–4. Understanding such hidden potential has major implications for protein design and evolutionary forecasting5–7, but has been limited by a lack of systematic efforts to identify potentiating mutations8,9. Here, through the comprehensive analysis of a bacterial toxin-antitoxin system, we identified all possible single substitutions in the toxin that enable it to tolerate otherwise interface-disrupting mutations in its antitoxin. Strikingly, the majority of enabling mutations in the toxin do not contact, and promote tolerance non-specifically to, many different antitoxin mutations, despite covariation in homologs occurring primarily between specific pairs of contacting residues across the interface. In addition, the enabling mutations we identified expand future mutational paths that both maintain old toxin-antitoxin interactions and form new ones. These non-specific mutations are missed by widely used covariation and machine learning methods10,11. Identifying such enabling mutations will be critical for ensuring continued binding of therapeutically relevant proteins, such as antibodies, aimed at evolving targets12–14.