Author Correction: GRAFENE: Graphlet-based alignment-free network approach integrates 3D structural and sequence (residue order) data to improve protein structural comparison.

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GRAFENE: Graphlet-based alignment-free network approach integrates 3D structural and sequence (residue order) data to improve protein structural comparison.

Initial protein structural comparisons were sequence-based. Since amino acids that are distant in the sequence can be close in the 3-dimensional (3D) structure, 3D contact approaches can complement sequence approaches. Traditional 3D contact approaches study 3D structures directly and are alignment-based.

Widespread position-specific conservation of synonymous rare codons within coding sequences.

Synonymous rare codons are considered to be sub-optimal for gene expression because they are translated more slowly than common codons. Yet surprisingly, many protein coding sequences include large clusters of synonymous rare codons. Rare codons at the 5' terminus of coding sequences have been shown to increase translational efficiency.

Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump.

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for the development of effective EPIs, especially in light of constantly emerging resistance.

DegP Chaperone Suppresses Toxic Inner Membrane Translocation Intermediates.

The periplasm of Gram-negative bacteria includes a variety of molecular chaperones that shepherd the folding and targeting of secreted proteins. A central player of this quality control network is DegP, a protease also suggested to have a chaperone function. We serendipitously discovered that production of the Bordetella pertussis autotransporter virulence protein pertactin is lethal in Escherichia coli ΔdegP strains.

Roles for Synonymous Codon Usage in Protein Biogenesis.

Owing to the degeneracy of the genetic code, a protein sequence can be encoded by many different synonymous mRNA coding sequences. Synonymous codon usage was once thought to be functionally neutral, but evidence now indicates it is shaped by evolutionary selection and affects other aspects of protein biogenesis beyond specifying the amino acid sequence of the protein. Synonymous rare codons, once thought to have only negative impacts on the speed and accuracy of translation, are now known to play an important role in diverse functions, including regulation of cotranslational folding, covalent modifications, secretion, and expression level.

Of linkers and autochaperones: an unambiguous nomenclature to identify common and uncommon themes for autotransporter secretion.

Autotransporter (AT) proteins provide a diverse array of important virulence functions to Gram-negative bacterial pathogens, and have also been adapted for protein surface display applications. The 'autotransporter' moniker refers to early models that depicted these proteins facilitating their own translocation across the bacterial outer membrane. Although translocation is less autonomous than originally proposed, AT protein segments upstream of the C-terminal transmembrane β-barrel have nevertheless consistently been found to contribute to efficient translocation and/or folding of the N-terminal virulence region (the 'passenger').

Expanding Anfinsen's principle: contributions of synonymous codon selection to rational protein design.

Anfinsen's principle asserts that all information required to specify the structure of a protein is encoded in its amino acid sequence. However, during protein synthesis by the ribosome, the N-terminus of the nascent chain can begin to fold before the C-terminus is available. We tested whether this cotranslational folding can alter the folded structure of an encoded protein in vivo, versus the structure formed when refolded in vitro.

An alternative outer membrane secretion mechanism for an autotransporter protein lacking a C-terminal stable core.

Autotransporter (AT) proteins are a broad class of virulence factors from Gram-negative pathogens. AT outer membrane (OM) secretion appears simple in many regards, yet the mechanism that enables transport of the central AT 'passenger' across the OM remains unclear. OM secretion efficiency for two AT passengers is enhanced by approximately 20 kDa stable core at the C-terminus of the passenger, but studies on a broader range of AT proteins are needed in order to determine whether a stability difference between the passenger N- and C-terminus represents a truly common mechanistic feature.

Folding the proteome.

Protein folding is an essential prerequisite for protein function and hence cell function. Kinetic and thermodynamic studies of small proteins that refold reversibly were essential for developing our current understanding of the fundamentals of protein folding mechanisms. However, we still lack sufficient understanding to accurately predict protein structures from sequences, or the effects of disease-causing mutations.