The PA14 domain, a conserved all-β domain in bacterial toxins, enzymes, adhesins and signaling molecules

doi:10.1016/j.tibs.2004.05.002

Trends in Biochemical Sciences

Volume 29, Issue 7, July 2004, Pages 335-339

https://doi.org/10.1016/j.tibs.2004.05.002 Get rights and content

Abstract

Iterative database searches starting from a domain insert sequence in bacterial β-glucosidases reveals the presence of a conserved domain shared by a wide variety of bacterial and eukaryotic proteins. These include other glycosidases, glycosyltransferases, proteases, amidases, adhesins, and bacterial toxins such as anthrax protective antigen (PA). The domain also occurs in the mammalian protein fibrocystin, mutation of which leads to autosomal-recessive polycystic kidney and hepatic disease. The crystal structure of PA shows that this domain (named PA14 after its location in the PA₂₀ pro-peptide) has a β-barrel architecture. A PA14 sequence alignment suggests a binding function, rather than a catalytic role, whereas the PA14 domain distribution is compatible with carbohydrate binding.

Section snippets

Domain definition

PSI–BLAST search of the NCBI non-redundant protein database (http://www.ncbi.nlm.nih.gov) using the insertion sequence of the A. tumefaciens β-glucosidase (residues 361–560 of SWISS-PROT P27034) as the query and inclusion E-value of 0.001 converged after nine iterations retrieving 132 proteins (Figure 1), including a Bacteroides thetaiotaomicron genomic [12] sequence BT2948 protein (GenBank accession AAO78054), which contains an insertion of the same domain (hereafter referred to as PA14

Domain architectures

Comparisons of the retrieved sequences against Pfam [6], SMART [18] and CDD [19] domain databases revealed many diverse domain combinations involving the PA14 domain (Figure 2). Most of the experimentally characterized PA14-containing proteins are involved in carbohydrate binding and/or metabolism (Figure 2), including glycoside hydrolase domains of families 2, 3, 10, 20 and 31 in the classification of Coutinho and Henrissat (http://afmb.cnrs-mrs.fr/~cazy/CAZY/index.html) and the recently

Domain function

Taken together, several lines of evidence suggest that the PA14 domain could be a novel carbohydrate-binding module:

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The PA14 domain is combined in a mosaic manner with various catalytic or non-catalytic domains directly or indirectly implicated in binding carbohydrate or peptidoglycan.
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For the yeast flocculins, carbohydrate binding has been demonstrated for a region overlapping the PA14 domain [21].
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The notion that the PA14 β-sandwich domain might have a carbohydrate-binding function is also

Future perspectives

The hypothesis that the PA14 domain binds carbohydrates raises interesting possibilities about its participation in anthrax toxin activation. Simple hydrolysis of the PA₂₀–PA₆₃ bond in intact PA is insufficient in itself to give subunit separation [14], which raises the question of what drives separation of the PA₂₀ and PA₆₃ in vivo. Attachment of the PA14 domain of the PA₂₀ fragment to an extracellular matrix component could provide an explanation for this apparent inconsistency and offer an

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Trends in Biochemical Sciences

Protein Sequence MotifThe PA14 domain, a conserved all-β domain in bacterial toxins, enzymes, adhesins and signaling molecules

Abstract

Section snippets

Domain definition

Domain architectures

Domain function

Future perspectives

Am. J. Hum. Genet.

Genomics

J. Biol. Chem.

J. Mol. Biol.

Curr. Biol.

Sequence and transcription of the β-glucosidase gene of Kluyveromyces fragilis cloned in Saccharomyces cerevisiae

Curr. Genet.

Cloning and sequencing of an Agrobacterium tumefaciens β-glucosidase gene involved in modifying a vir-inducing plant signal molecule

J. Bacteriol.

Cloning and expression of Clostridium stercorarium cellulase genes in Escherichia coli

Biotechnol. Lett.

Thermotoga neapolitana bglB gene, upstream of lamA, encodes a highly thermostable β-glucosidase that is a laminaribiase

Microbiol.

A classification of glycosyl hydrolases based on amino acid sequence similarities

Biochem. J.

The Pfam protein families database

Nucleic Acids Res.

An adhesin of the yeast pathogen Candida glabrata mediating adherence to human epithelial cells

Science

Modular domain structure in the Candida glabrata adhesin Epa1p, a β-1,6 glucan-cross-linked cell wall protein

Mol. Microbiol.

The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein

Nat. Genet.

A genomic view of the human-Bacteroides thetaiotaomicron symbiosis

Science

Protein Sequence Motif
The PA14 domain, a conserved all-β domain in bacterial toxins, enzymes, adhesins and signaling molecules