Efflux Pumps Represent Possible Evolutionary Convergence onto the β-Barrel Fold

Franklin, Meghan Whitney; Nepomnyachiy, Sergey; Feehan, Ryan; Ben‐Tal, Nir; Kolodny, Rachel; Slusky, Joanna S.G.

doi:10.1016/j.str.2018.06.007

Cited by 21 publications

(33 citation statements)

References 46 publications

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“…Since most repeat proteins do not have function as individual domains, it has been hypothesized that many repeat proteins were originally homo-oligomers (Ponting and Russell, 2000). This hypothesis supports the idea of the primordial barrel as a multi-chain beta barrel like YadA (Franklin et al, 2018a): a trimeric adhesion protein, where each chain contributes four strands (a double hairpin) to create a 12-stranded barrel.…”

Section: Discussionsupporting

confidence: 83%

“…We compiled a data set of 138 OMBBs at <85% sequence similarity, 118 of which share <50% sequence similarity (Franklin et al, 2018a; Franklin and Slusky, 2018b). To determine evolutionary relationships, we selected homologues to the structurally solved proteins from a database of 279,715 nonredundant sequences and generated hidden Markov model (HMM) profile alignments.…”

Section: Resultsmentioning

confidence: 99%

“…We use the E-value ≤10 −3 because that value is the most widely used to infer homology, that is evolution from a common ancestor, (Pearson, 2013) and because it cleanly distinguished the prototypical barrels from other groups of OMBBs. The other groups of OMBBs, such as the efflux pumps, assembly barrels, and Fim/usher proteins, are described more fully elsewhere (Franklin et al, 2018a).…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial OMBBs each have an even number of strands between 8 and 26. The addition of each hairpin (two strands connected by a loop) imparts an extra 1.66 Å to the radius (Franklin et al, 2018a) in the same way that the addition of an extra two planks to a cask widens the barrel’s radius by a consistent amount. Changing the radius of a barrel alters pore specificity to accommodate or reject molecules for passage based on size.…”

Section: Introductionmentioning

confidence: 99%

“…Although there are few instances in which the membrane barrel topology was converged upon independently (Franklin et al, 2018a), most OMBBs are homologous as shown by sequence alignments (Remmert et al, 2010; Reddy and Saier, 2016). Like all diversification events, the diversification that maintained this common fold while accommodating diverse function occured through a combination of amplification, recombination, and the accretion of mutations.…”

Section: Introductionmentioning

confidence: 99%

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Evolutionary pathways of repeat protein topology in bacterial outer membrane proteins

Franklin

Nepomnyachyi

Feehan

et al. 2018

eLife

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Outer membrane proteins (OMPs) are the proteins in the surface of Gram-negative bacteria. These proteins have diverse functions but a single topology: the β-barrel. Sequence analysis has suggested that this common fold is a β-hairpin repeat protein, and that amplification of the β-hairpin has resulted in 8–26-stranded barrels. Using an integrated approach that combines sequence and structural analyses, we find events in which non-amplification diversification also increases barrel strand number. Our network-based analysis reveals strand-number-based evolutionary pathways, including one that progresses from a primordial 8-stranded barrel to 16-strands and further, to 18-strands. Among these pathways are mechanisms of strand number accretion without domain duplication, like a loop-to-hairpin transition. These mechanisms illustrate perpetuation of repeat protein topology without genetic duplication, likely induced by the hydrophobic membrane. Finally, we find that the evolutionary trace is particularly prominent in the C-terminal half of OMPs, implicating this region in the nucleation of OMP folding.

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Section: Discussionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evolutionary pathways of repeat protein topology in bacterial outer membrane proteins

Franklin

Nepomnyachyi

Feehan

et al. 2018

eLife

Self Cite

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Outer membrane β‐barrel structure prediction through the lens of AlphaFold2

2023

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Most proteins found in the outer membrane of gram‐negative bacteria share a common domain: the transmembrane β‐barrel. These outer membrane β‐barrels (OMBBs) occur in multiple sizes and different families with a wide range of functions evolved independently by amplification from a pool of homologous ancestral ββ‐hairpins. This is part of the reason why predicting their three‐dimensional (3D) structure, especially by homology modeling, is a major challenge. Recently, DeepMind's AlphaFold v2 (AF2) became the first structure prediction method to reach close‐to‐experimental atomic accuracy in CASP even for difficult targets. However, membrane proteins, especially OMBBs, were not abundant during their training, raising the question of how accurate the predictions are for these families. In this study, we assessed the performance of AF2 in the prediction of OMBBs and OMBB‐like folds of various topologies using an in‐house‐developed tool for the analysis of OMBB 3D structures, and barrOs. In agreement with previous studies on other membrane protein classes, our results indicate that AF2 predicts transmembrane β‐barrel structures at high accuracy independently of the use of templates, even for novel topologies absent from the training set. These results provide confidence on the models generated by AF2 and open the door to the structural elucidation of novel transmembrane β‐barrel topologies identified in high‐throughput OMBB annotation studies or designed de novo.

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