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Bioactive Peptides Hidden in Human Salivary Proteins

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Bioactive Peptides Hidden in Human Salivary Proteins Journal of Oral Biosciences 59 (2017) 71–79 Contents lists available at ScienceDirect Journal of Oral Biosciences journal homepage: www.elsevier.com/locate/job Review Bioactive peptides hidden in human salivary proteins Eiichi Saitoh a,n, Masayuki Taniguchi b, Akihito Ochiai b, Tetsuo Kato c, Akane Imai d, Satoko Isemura d a Graduate School of Technology, Niigata Institute of Technology, 1719 Fujihashi, Kashiwazaki, Niigata 945-1195, Japan b Department of Materials Science and Technology, Graduate School of Science and Technology, Niigata University, Niigata 950-2181, Japan c Laboratory of Chemistry, Tokyo Dental College, Tokyo 101-0062, Japan d Department of Dental Hygiene, The Nippon Dental University College at Niigata, Niigata 951-8580, Japan article info abstract Article history: Background: Extensive peptidomic studies of human saliva have resulted in considerable advances in the field Received 28 September 2016 of proteomics. As the next generation in salivary research, a comprehensive understanding of the biological Received in revised form functions of in vivo peptides generated by proteolysis in the oral cavity has been long awaited. A cyclopedic 4 November 2016 functional analysis of salivary peptides may bring promising therapeutic agents and novel clinical applications. Accepted 17 November 2016 Highlight: (1) This review article refers to bioactive peptides hidden in salivary parent proteins. (2) Functions of Available online 5 December 2016 the peptides as anti-microbial, anti-viral, wound-closing, and anti-pain are described. (3) Biological sig- Keywords: nificances of the repeated structures in salivary proline-rich proteins are emphasized. Human salivary proteome Conclusion: Human salivary proteins have the ability to generate bioactive peptides upon proteolytic cleavage. Bioactive peptides in salivary proteins & 2016 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved. Antimicrobial activity Wound-closing factor Anti-cancer activity Contents 1. Introduction.........................................................................................................71 2. A gift from the human genome project to salivary research. 72 2.1. Multiple proteins are produced by one gene . 72 2.2. Two gene clusters encoding major salivary proteins . 73 2.2.1. The gene cluster on chromosome 4q13.3 . 73 2.2.2. The gene cluster on chromosome 12p13.2 . 74 3. Bioactive peptides hidden in salivary proteins. 75 3.1. Bioactive peptides in statherin, histatin 1, and histatin 3 . 75 3.2. Bioactive peptides in P-B, P-B1, and PBLP . 76 3.3. Bioactive peptides in salivary mucins. 77 3.4. Bioactive peptides in aPRPs, bPRPs, and gPRPs . 77 4. Concluding remarks. 77 Ethicalapproval..........................................................................................................77 Conflictofinterest........................................................................................................77 Acknowledgments. 78 References..............................................................................................................78 Abbreviations: N-, amino-; C-, carboxyl-; PRP, proline rich protein; a, acidic; b, basic; g, glycosylated n Corresponding author. E-mail address: [email protected] (E. Saitoh). http://dx.doi.org/10.1016/j.job.2016.11.005 1349-0079/& 2016 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved. 72 E. Saitoh et al. / Journal of Oral Biosciences 59 (2017) 71–79 Fig. 1. Chromosomal localization of the genes encoding salivary (or lacrimal) proteins. Open squares indicate noncoding exon regions. Closed squares denote coding exon regions. Gray squares indicate exons encoding the PRPs-specific repeating unit G(P)nG(K/R)PQ and its related sequences. 1. Introduction dilution and cleaning, digestion, lubrication, and protection of tooth enamel are granted by parent proteins and occasionally their pro- To develop diagnostic systems based on human salivary protein cessed forms [7]. These biological functions are related not only to components, extensive proteomic and peptidomic studies have been oral health, but also to systemic health. The environment of the oral performed involving whole saliva (WS), parotid saliva (PS), sub- cavity, the “port of entry” of the gastrointestinal tract, is likened to a mandibular/sublingual saliva (SM/SL-S), and exosomes in WS over high-performance and elaborate incubator because the pH and tem- the past decade. Previous studies of the human salivary proteome perature in the cavity and gastrointestinal tract are precisely con- identified 914 proteins in the PS proteome [1],917intheSM/SL-S trolled. The oral cavity contains culture media rich in nutrients sup- proteome [1], 491 in the parotid exosome [2], 187 in two types of plied by dietary foods, in which notable proteolytic events take place exosomes in WS [3], and 56 in minor salivary gland secretions [4]. on salivary and dietary proteins. The predominate peptide fragments WS proteins in the oral cavity predominantly originate from three present in WS have been reported to be derived from aRRPs, bPRPs, major salivary glands: the parotid, submandibular, and sublingual gPRP,P-B,statherin,andhistatins[8]. Oppenheim et al. [8] have dis- glands. Many proteins have been identified in WS, including acidic covered unique proteases in WS that cleave preferentially after a (a) proline-rich proteins (PRPs), basic (b) PRPs, glycosylated (g) PRPs, glutamine residue for the tripeptide sequence -KPQ- in aPRPs, bPRPs, P-B, cystatins, histatins, statherin, mucous glycoproteins, mucin 5 and gPRP. The PRP-specificrepeatingunit,G(P)nG(K/R)PQ, and its (MG1), mucin 7 (MG2), immunoglobulins, amylase, and agglutinin related sequences are excised by proteases. These excised peptides [5]. Multiple variations based on genetic polymorphisms have been display completely different functions than the parent proteins [9,10] observed for each protein [6]. and were of unknown relevance until now. It has been gradually re- According to the NCBI gene database (http://www.ncbi.nlm.nih.gov/ cognized that the peptide fragments created by proteases from oral gene/), salivary proteins, including statherin, histatin 3, histatin 1, P-B1, epithelial cells, bacteria, and a serum-like gingival crevicular transu- P-B, BPLP, and mucin 7, are encoded by a set of clustered genes loca- date, play important roles in both the oral cavity and further down- lized on chromosome 4 [Cytogenetic location: 4q13.3, Genomic stream in the alimentary canal. Despite the identification of more coordinates: 4: 69,995,930-70,482,997; - STATH (encoding statherin) - than 4000 different salivary peptides and protein species [11],phy- HTN3 (alias HIS2; encoding histatin 3) - HTN1 (HIS1;histatin1)-PBI siological functions of salivary peptides are beginning to be under- (SMR3A or PROL5; P-B1 or SMR3A) - PBII (SMR3B or PROL3; P-B or stood and only recently have applications of these peptides been SMR3B) - OPRPN (PROL1; basic proline-rich lacrimal protein BPLP) - examined. MUC7 (mucin 7) -]. Moreover, lacrimal proline-rich protein (LPRP), two In this review article, we summarize the bioactive peptides aPRPs, one bPRP, and three gPRPs are encoded by another gene cluster identified so far that are hidden in major human salivary proteins. [Cytogenetic location: 12p13.2, Genomic coordinates: 12: 10,845,849- 11,501,041; - PRR4 (alias PROL4; encoding LPRP) - PRH1 (encoding aPRP) - PRH2 (aPRP) - PRB3 (gPRP) - PRB4 (gPRP) - PRB1 (bPRP) - PRB2 2. A gift from the human genome project to salivary research (gPRP) -]. The PRH2 geneislocatedintheforwardstrandofchromo- some 4 but the other six genes are in the reverse strand. 2.1. Multiple proteins are produced by one gene Most of the established biological functions of saliva such as an- timicrobial properties, wound repairing, pain control, buffering, Brief maps of two gene clusters encoding major salivary proteins E. Saitoh et al. / Journal of Oral Biosciences 59 (2017) 71–79 73 Fig. 2. Summary of biological information for statherin, histatin 3, histatin 4, P-B1, and P-B. Nomenclature of each gene, UniProt/Swiss-Prot number, and amino acid sequence of each protein are present in the NCBI gene and UniProt/Swiss-Prot database. The signal sequence for each protein is shown in italics. The N-terminal and C-terminal amino acid residues for each protein are numbered. Antimicrobial peptide sequence in statherin (P02808) is indicated by a dotted underline. The histatin 5 sequence in histatin 3 (P15516) is indicated by a triple underline. The minimal domain required for wound healing activity in histatin 1 (P15515) is indicated by a solid underline. The opiorphin homolog (QRGPR) in P-B1 (Q99954), P-B (P02814), and P-B variant (Q508X8Q504 Â 8) is indicated by a double underline. The possible N-glyco- sylation site (N-C-S) in the amino acid sequence of P-B variant is underlined. Sugar chain is indicated by duplex-closed circles. on chromosome 4q13.3 and chromosome 12p13.2 are illustrated in amino acid sequences encoded by the genes (STATH, HTN3, HTN1, Fig. 1 and are based on data resulting from the human genome pro- PBI, and PBII) are given in Fig. 2. In the same manner, Fig. 3 shows ject (http://www.ncbi.nlm.nih.gov/gene/). These achievements re- the amino acid sequences encoded by OPRPN and MUC7. STATH, vealed that alternative splicing causes multiple exon combinations, HTN3, and HTN1 are composed of six exons that are thought to be including coding- and non-coding DNA sequences, thereby many derived
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