Identification of the Bacteria-binding Peptide Domain on Salivary Agglutinin (gp-340/DMBT1), a Member of the Scavenger Receptor Cysteine-rich Superfamily

Bikker, Floris J.; Ligtenberg, A.J.M.; Nazmi, Kamran; Veerman, E.C.I.; Hof, Wim van ’t; Bolscher, Jan G. M.; Poustka, Annemarie; Amerongen, A. van Nieuw; Mollenhauer, Jan

doi:10.1074/jbc.m203788200

Cited by 147 publications

(194 citation statements)

References 39 publications

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“…This shows that both gp-340 and CRP-ductin are cable of binding bacteria in the absence of SP-D, indicating that these molecules could have a role in the microbial clearance of potentially pathogenic microorganisms alone or in combination with SP-D. The binding site of the agglutinin-bacteria interaction has recently been mapped to a SRCR domain [28], making it likely that its also a SRCR domain in CRP-ductin that interacts with bacteria.…”

Section: Discussionmentioning

confidence: 95%

CRP‐ductin, the mouse homologue of gp‐340/deleted in malignant brain tumors 1 (DMBT1), binds gram‐positive and gram‐negative bacteria and interacts with lung surfactant protein D

et al. 2003

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CRP-ductin is a protein expressed mainly by mucosal epithelial cells in the mouse. Sequence homologies indicate that CRP-ductin is the mouse homologue of human gp-340, a glycoprotein that agglutinates microorganisms and binds the lung mucosal collectin surfactant protein-D (SP-D). Here we report that purified CRP-ductin binds human SP-D in a calcium-dependent manner and that the binding is not inhibited by maltose. The same properties have previously been observed for gp-340 binding of SP-D. CRP-ductin also showed calcium-dependent binding to both gram-positive and -negative bacteria. A polyclonal antibody raised against gp-340 reacted specifically with CRP-ductin in Western blots. Immunoreactivity to CRP-ductin was found in the exocrine pancreas, in epithelial cells throughout the gastrointestinal tract and in the parotid ducts. A panel of RNA preparations from mouse tissues was screened for CRP-ductin and SP-D expression by reverse transcription-PCR. The pancreas was the main site of synthesis of CRP-ductin, but transcripts were also readily amplified from salivary gland, the gastrointestinal tract, liver, testis, uterus and lung. Lung was the main site of synthesis of SP-D, but transcripts were also amplified from uterus, salivary gland, thymus, thyroid gland, pancreas and testis. We conclude that CRP-ductin is the mouse homologue of human gp-340 and that its capacity to bind SP-D as well as gramnegative and gram-positive bacteria suggests a role in mucosal immune defense.

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Section: Discussionmentioning

confidence: 95%

CRP‐ductin, the mouse homologue of gp‐340/deleted in malignant brain tumors 1 (DMBT1), binds gram‐positive and gram‐negative bacteria and interacts with lung surfactant protein D

et al. 2003

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“…Furthermore, it has been suggested that the frequency of high copy number alleles of the salivary amylase gene AMY1 has increased by natural selection in populations that eat a carbohydrate-rich diet (20). DMBT1 SAG mostly consists of an array of scavenger receptor cysteine-rich (SRCR) domains which bind bacteria, including S. mutans (21) and promote their adherence to hydroxyapatite of the tooth (22,23), which is critical for the cariogenic activity of the bacteria. The canonical DMBT1 gene annotated in the hg19 human genome assembly has 13 repeats each containing a SRCR domain (Fig.…”

Section: Significancementioning

confidence: 99%

Evolution of the rapidly mutating human salivary agglutinin gene ( DMBT1 ) and population subsistence strategy

Polley

Louzada

Forni

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The dietary change resulting from the domestication of plant and animal species and development of agriculture at different locations across the world was one of the most significant changes in human evolution. An increase in dietary carbohydrates caused an increase in dental caries following the development of agriculture, mediated by the cariogenic oral bacterium Streptococcus mutans. Salivary agglutinin [SAG, encoded by the deleted in malignant brain tumors 1 (DMBT1) gene] is an innate immune receptor glycoprotein that binds a variety of bacteria and viruses, and mediates attachment of S. mutans to hydroxyapatite on the surface of the tooth. In this study we show that multiallelic copy number variation (CNV) within DMBT1 is extensive across all populations and is predicted to result in between 7-20 scavenger-receptor cysteinerich (SRCR) domains within each SAG molecule. Direct observation of de novo mutation in multigeneration families suggests these CNVs have a very high mutation rate for a protein-coding locus, with a mutation rate of up to 5% per gamete. Given that the SRCR domains bind S. mutans and hydroxyapatite in the tooth, we investigated the association of sequence diversity at the SAG-binding gene of S. mutans, and DMBT1 CNV. Furthermore, we show that DMBT1 CNV is also associated with a history of agriculture across global populations, suggesting that dietary change as a result of agriculture has shaped the pattern of CNV at DMBT1, and that the DMBT1-S. mutans interaction is a promising model of host-pathogenculture coevolution in humans.copy number variation | agriculture | DMBT1 | mutation | structural variation

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“…Inhibition of gp340 Binding-Both the carbohydrate portions of gp340 and its peptide core have been reported to mediate microbial binding (18,32). In order to characterize the structures involved in Spy0843 binding, we first tested the effects of various monosaccharides and treatments affecting the glycopart of gp340 on r0843 binding.…”

Section: Inhibition Of S Pyogenes Binding To Gp340 By Lrr Proteins-mentioning

confidence: 99%

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

Loimaranta¹,

Hytönen

Pulliainen

et al. 2009

Journal of Biological Chemistry

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Scavenger receptors are innate immune molecules recognizing and inducing the clearance of non-host as well as modified host molecules. To recognize a wide pattern of invading microbes, many scavenger receptors bind to common pathogenassociated molecular patterns, such as lipopolysaccharides and lipoteichoic acids. Similarly, the gp340/DMBT1 protein, a member of the human scavenger receptor cysteine-rich protein family, displays a wide ligand repertoire. The peptide motif VEVLXXXXW derived from its scavenger receptor cysteine-rich domains is involved in some of these interactions, but most of the recognition mechanisms are unknown. In this study, we used mass spectrometry sequencing, gene inactivation, and recombinant proteins to identify Streptococcus pyogenes protein Human gp340, also known as DMBT1 (deleted in malignant brain tumors 1), belongs to the innate immune protein family of scavenger receptor cysteine-rich (SRCR) 2 proteins, all of which contain one or more evolutionarily conserved SRCR domain linked to other conserved protein domains (1, 2). Many of these proteins serve as pattern recognition receptors for innate immunity. gp340 is expressed by epithelial cells and cells of the immune system, and its expression is up-regulated after inflammatory stimuli (3, 4). It inhibits bacterial invasion to epithelial cells and the secretion of proinflammatory cytokines (5-7).Thus, it appears to be an important mediator of host immune responses to various microbes and was recently linked to Crohn disease, a human inflammatory bowel disease (8). gp340 is also found in human secretions like tears and saliva, and the salivary form has long been known as salivary agglutinin, which is an important molecule in oral biofilm formation and is suggested to have a role in dental caries development (9 -12). The mechanisms of gp340 action in these different biological contexts are not known. Common to all scavenger receptors, the ligand repertoire of gp340 is wide; it binds many different types of bacteria as well as viruses (10,13,14). The wide ligand recognition pattern of scavenger receptors is thought to be based on the recognition of common microbial structures, such as lipopolysaccharides and lipoteichoic acids, but in the case of gp340, specific bacterial surface proteins are reported to be involved in the interactions characterized (15-18). Because the importance of gp340/salivary agglutinin in the oral environment has been evident for a long time, most of our knowledge of gp340-microbial interactions is from studies with oral bacteria. For example, viridans streptococci, such as Streptococcus mutans and Streptococcus gordonii, interact with saliva gp340 via their surface proteins AgI/II and the sialic acid-binding Hsa or GspB adhesin. In these interactions, gp340 shows a peculiar fluid phase versus surfaceadsorbed behavior, as evidenced by AgI/II polypeptides primarily mediating aggregation of bacteria by fluid phase gp340, whereas the Hsa adhesin primarily mediates adhesion of S. gordonii to surface-bound gp340 (18)...

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Identification of the Bacteria-binding Peptide Domain on Salivary Agglutinin (gp-340/DMBT1), a Member of the Scavenger Receptor Cysteine-rich Superfamily

Cited by 147 publications

References 39 publications

CRP‐ductin, the mouse homologue of gp‐340/deleted in malignant brain tumors 1 (DMBT1), binds gram‐positive and gram‐negative bacteria and interacts with lung surfactant protein D

CRP‐ductin, the mouse homologue of gp‐340/deleted in malignant brain tumors 1 (DMBT1), binds gram‐positive and gram‐negative bacteria and interacts with lung surfactant protein D

Evolution of the rapidly mutating human salivary agglutinin gene ( DMBT1 ) and population subsistence strategy

Leucine-rich Repeats of Bacterial Surface Proteins Serve as Common Pattern Recognition Motifs of Human Scavenger Receptor gp340

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