Discovery of fibrillar adhesins across bacterial species

Monzon, Vivian; Lafita, Aleix; Bateman, Alex

doi:10.1186/s12864-021-07586-2

Cited by 16 publications

(48 citation statements)

References 45 publications

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“…The known stalk and adhesive domains are the strongest feature in the classification decision approach. This bias is due to the positive training data, which was selected from the prior domain-based discovery approach [7]. Other strong features were the protein length, which is required to overcome the bacterial cell surface, and the amino acid composition of the protein sequences.…”

Section: Discussionmentioning

confidence: 99%

“…The jackhmmer search yielded the DUF11 stalk domain. This is strengthened by the predicted structures, which strongly resemble stalk domains, nevertheless leaving open whether these stalk domains can be involved in the binding function [7]. One possibility is that the function of these proteins is not adhesive, but to act as a steric regulator altering the access of other adhesive proteins to binding partners.…”

Section: Clusters Unlikely To Be Adhesive Domainsmentioning

confidence: 95%

“…We decided to concentrate on the Firmicute and Actinobacteria phyla in this study. Fibrillar adhesins are best studied in Firmicutes and the cell surface composition and FA-like protein architecture of the Actinobacteria resembles those of the Firmicutes [2,3,7]. We created a positive training set based on the FA-like proteins identified in our previous study [7].…”

Section: Random Forest Classificationmentioning

confidence: 99%

“…Fibrillar adhesins are best studied in Firmicutes and the cell surface composition and FA-like protein architecture of the Actinobacteria resembles those of the Firmicutes [2,3,7]. We created a positive training set based on the FA-like proteins identified in our previous study [7]. For the negative training set we randomly selected non-FA-like proteins from eight Firmicute and Actinobacteria Reference Proteomes, in which FA-like proteins were detected in our previous study [7].…”

Section: Random Forest Classificationmentioning

confidence: 99%

“…One example is the adhesive protein Adhesin_P1, which expresses two adhesive domains, one N-terminal folding towards the stalk and a second one in the middle, which is presented at the distal end in the final structural conformation [16]. Another example are proteins with repeating adhesive domains, e.g., SSURE (Pfam:PF11966), assumed to function as both a stalk and adhesive binding domain [7].…”

Section: Analysis Of Predicted Fa-like Proteinsmentioning

confidence: 99%

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Large Scale Discovery of Microbial Fibrillar Adhesins and Identification of Novel Members of Adhesive Domain Families

Monzon¹,

Bateman²

2021

Preprint

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Fibrillar adhesins are bacterial cell surface proteins that mediate interactions with host cells during colonisation and with other bacteria during biofilm formation. These proteins are characterised by a stalk that projects the adhesive domain closer to the binding target. Fibrillar adhesins evolve quickly and thus can be difficult to computationally identify, yet they represent an important component for understanding bacterial host interactions. To detect novel fibrillar adhesins we developed a random forest prediction approach based on common characteristics we identified for this protein class. We applied this approach to Firmicute and Actinobacterial proteomes, yielding over 4,000 confidently predicted fibrillar adhesins. To verify the approach we investigated predicted fibrillar adhesins that lacked a known adhesive domain. Based on these proteins, we identified 21 sequence clusters representing potential novel adhesive domains. We used AlphaFold to verify that 14 clusters showed structural similarity to known adhesive domains such as the TED domain. Overall our study has made a significant contribution to the number of known fibrillar adhesins and has enabled us to identify novel adhesive domain families involved in the bacterial pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Clusters Unlikely To Be Adhesive Domainsmentioning

confidence: 95%

Section: Random Forest Classificationmentioning

confidence: 99%

Section: Random Forest Classificationmentioning

confidence: 99%

Section: Analysis Of Predicted Fa-like Proteinsmentioning

confidence: 99%

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Large Scale Discovery of Microbial Fibrillar Adhesins and Identification of Novel Members of Adhesive Domain Families

Monzon¹,

Bateman²

2021

Preprint

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Domain shuffling of a highly mutable ligand‐binding fold drives adhesin generation across the bacterial kingdom

et al. 2023

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Bacterial fibrillar adhesins are specialized extracellular polypeptides that promote the attachment of bacteria to the surfaces of other cells or materials. Adhesin-mediated interactions are critical for the establishment and persistence of stable bacterial populations within diverse environmental niches and are important determinants of virulence. The fibronectin (Fn)-binding fibrillar adhesin CshA, and its paralogue CshB, play important roles in host colonization by the oral commensal and opportunistic pathogen Streptococcus gordonii. As paralogues are often catalysts for functional diversification, we have probed the early stages of structural and functional divergence in Csh proteins by determining the X-ray crystal structure of the CshB adhesive domain NR2 and characterizing its Fn-binding properties in vitro. Despite sharing a common fold, CshB_NR2 displays an $1.7-fold reduction in Fn-binding affinity relative to CshA_NR2. This correlates with reduced electrostatic charge in the Fn-binding cleft. Complementary bioinformatic studies reveal that homologues of CshA/B_NR2 domains are widely distributed in both Gram-positive and Gramnegative bacteria, where they are found housed within functionally cryptic multidomain polypeptides. Our findings are consistent with the classification of Csh adhesins and their relatives as members of the recently defined polymer adhesin domain (PAD) family of bacterial proteins.

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Adhesin domains responsible for binding bacteria to surfaces they colonize project outwards from companion split domains

Graham,

Hansen,

Yang

et al. 2024

Proteins

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Bacterial adhesins attach their hosts to surfaces that the bacteria will colonize. This surface adhesion occurs through specific ligand‐binding domains located towards the distal end of the long adhesin molecules. However, recognizing which of the many adhesin domains are structural and which are ligand binding has been difficult up to now. Here we have used the protein structure modeling program AlphaFold2 to predict structures for these giant 0.2‐ to 1.5‐megadalton proteins. Crystal structures previously solved for several adhesin regions are in good agreement with the models. Whereas most adhesin domains are linked in a linear fashion through their N‐ and C‐terminal ends, ligand‐binding domains can be recognized by budding out from a companion core domain so that their ligand‐binding sites are projected away from the axis of the adhesin for maximal exposure to their targets. These companion domains are “split” in their continuity by projecting the ligand‐binding domain outwards. The “split domains” are mostly β‐sandwich extender modules, but other domains like a β‐solenoid can serve the same function. Bioinformatic analyses of Gram‐negative bacterial sequences revealed wide variety ligand‐binding domains are used in their Repeats‐in‐Toxin adhesins. The ligands for many of these domains have yet to be identified but known ligands include various cell‐surface glycans, proteins, and even ice. Recognizing the ligands to which the adhesins bind could lead to ways of blocking colonization by bacterial pathogens. Engineering different ligand‐binding domains into an adhesin has the potential to change the surfaces to which bacteria bind.

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Discovery of fibrillar adhesins across bacterial species

Cited by 16 publications

References 45 publications

Large Scale Discovery of Microbial Fibrillar Adhesins and Identification of Novel Members of Adhesive Domain Families

Large Scale Discovery of Microbial Fibrillar Adhesins and Identification of Novel Members of Adhesive Domain Families

Domain shuffling of a highly mutable ligand‐binding fold drives adhesin generation across the bacterial kingdom

Adhesin domains responsible for binding bacteria to surfaces they colonize project outwards from companion split domains

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