The whey acidic protein family: a new signature motif and three-dimensional structure by comparative modeling

Ranganathan, Shoba; Simpson, Kaylene J.; Shaw, Douglas J.; Nicholas, Kevin R.

doi:10.1016/s1093-3263(99)00023-6

Cited by 129 publications

(115 citation statements)

References 32 publications

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“…Of the two WFDC domains in WAP in eutherian milks, designated as DI and DII, only DII retains the characteristic N-terminal motif found in most WFDC domains (Lys-X-Gly-X-Cys-Pro, where X represents various amino acids); amino acid substitutions in this and other areas of DI may have altered the charge distribution, glycosylation sites, and conformation in such a way that original functions are no longer possible (Ranganathan et al, 1999). Monotreme and marsupial WAPs contain two to three WFDC domains, but of differing sequence and arrangement than eutherian WAPs (Sharp et al, 2007), and it is thought that they may retain functions lost in eutherians, but more evidence is required (Topcic et al, 2009).…”

Section: Evolution Of Milk Secretionmentioning

confidence: 99%

The evolution of milk secretion and its ancient origins

Oftedal

2012

Animal

196

142

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Lactation represents an important element of the life history strategies of all mammals, whether monotreme, marsupial, or eutherian. Milk originated as a glandular skin secretion in synapsids (the lineage ancestral to mammals), perhaps as early as the Pennsylvanian period, that is, approximately 310 million years ago (mya). Early synapsids laid eggs with parchment-like shells intolerant of desiccation and apparently dependent on glandular skin secretions for moisture. Mammary glands probably evolved from apocrine-like glands that combined multiple modes of secretion and developed in association with hair follicles. Comparative analyses of the evolutionary origin of milk constituents support a scenario in which these secretions evolved into a nutrient-rich milk long before mammals arose. A variety of antimicrobial and secretory constituents were co-opted into novel roles related to nutrition of the young. Secretory calcium-binding phosphoproteins may originally have had a role in calcium delivery to eggs; however, by evolving into large, complex casein micelles, they took on an important role in transport of amino acids, calcium and phosphorus. Several proteins involved in immunity, including an ancestral butyrophilin and xanthine oxidoreductase, were incorporated into a novel membrane-bound lipid droplet (the milk fat globule) that became a primary mode of energy transfer. An ancestral c-lysozyme lost its lytic functions in favor of a role as a-lactalbumin, which modifies a galactosyltransferase to recognize glucose as an acceptor, leading to the synthesis of novel milk sugars, of which free oligosaccharides may have predated free lactose. An ancestral lipocalin and an ancestral whey acidic protein four-disulphide core protein apparently lost their original transport and antimicrobial functions when they became the whey proteins b-lactoglobulin and whey acidic protein, which with a-lactalbumin provide limiting sulfur amino acids to the young. By the late Triassic period (ca 210 mya), mammaliaforms (mammalian ancestors) were endothermic (requiring fluid to replace incubatory water losses of eggs), very small in size (making large eggs impossible), and had rapid growth and limited tooth replacement (indicating delayed onset of feeding and reliance on milk). Thus, milk had already supplanted egg yolk as the primary nutrient source, and by the Jurassic period (ca 170 mya) vitellogenin genes were being lost. All primary milk constituents evolved before the appearance of mammals, and some constituents may have origins that predate the split of the synapsids from sauropsids (the lineage leading to 'reptiles' and birds). Thus, the modern dairy industry is built upon a very old foundation, the cornerstones of which were laid even before dinosaurs ruled the earth in the Jurassic and Cretaceous periods.Keywords: evolution, lactation, milk composition, casein, milk fat globule ImplicationsLactation has an evolutionary origin and biological context within which its secretory processes and milk constituents evolved. This revi...

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Section: Evolution Of Milk Secretionmentioning

confidence: 99%

The evolution of milk secretion and its ancient origins

Oftedal

2012

Animal

196

142

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“…The term 'whey acidic protein' is derived from the name given to a family of proteins, originally discovered in the whey fraction of mammalian milk. Whilst all these milk proteins are characterised by possession of two WAP domains, each comprising 50 aa [13], numerous other non-milk whey acidic proteins are now also known and these may have one or more 4DSCs. Amongst these non-milk whey acidic proteins are small secretory proteins with protease inhibitory properties or regulatory functions in growth, tissue differentiation or regulation and may sometimes be expressed in certain cancer states [14,15].…”

Section: Definition Of a Crustinmentioning

confidence: 99%

Crustins: Enigmatic WAP domain-containing antibacterial proteins from crustaceans

Smith

Fernandes²,

Kemp

et al. 2008

Developmental & Comparative Immunology

236

169

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Crustins are antibacterial proteins of ca 7-14 kDa with a characteristic four disulphide corecontaining whey acidic protein (WAP) domain, expressed by the circulating haemocytes of crustaceans.Over 50 crustin sequences have been now reported from a variety of decapods, including crabs, lobsters, shrimp and crayfish. Three main types seem to occur but all possess a signal sequence at the amino terminus and a WAP domain at the carboxyl end. Differences between types lie in the structure of the central region. Those crustins purified as the native protein or expressed recombinantly all kill Gram-positive bacteria, and gene studies have shown that they are constitutively expressed, often at high levels, but show no consistent patterns of change in expression following injection of bacteria. This variable response to infection is enigmatic but indicates that these proteins could perform additional functions, perhaps as immune regulators in recovery from wounding, trauma or physiological stress.Prof Kenneth Soderhall Co-Editor in Chief Developmental and Comparative Immunology Dear Kenneth I attach the revised manuscript for the invited review, Crustins: enigmatic WAP domaincontaining antibacterial proteins from crustaceans, for which all the referees comments have been addressed. Below is a summary of changes made.1. Two of the reviewers have issues with the SS tree (formerly Fig 2), with reviewer 2 making the point that the functional WAP domain will more usefully indicate relationships rather than the SS. We do not concur with the comment that the signal sequence (SS) tree is unnecessary but do accept that its placement in the article could be better and that it could be more fully discussed. Importantly, the SS radiation tree did not drive the 3-type classification, rather it was led by the overall domain organisation of the various types that we judged, from our starting definition, to be within the crustin 'family'. The region of variation is mainly in the 'central' region of the molecule, ie between the SS and WAP domain. We constructed the SS and WAP domain trees to test if the suggested classification was supported, independently by phylogenies within these regions. We believe that they do and the inclusion of both trees, rather than just a tree for the WAP domain, makes the case for the classification of crustins into Types I, II or III, even stronger. We have therefore retained the SS radiation tree but discuss it more fully in the section on 'Relationships' (new pages 11 & 12) rather than its former position. We prefer not to add species identifiers to the as these will make it very 'busy' and untidy. We feel that Accession numbers are more appropriate than species names. Please note we have slightly modified the annotations by leaving ambiguous sequences out of the clusters marked by dotted or dashed lines.2. Referee 1 correctly points out that the argument (beginning in the last paragraph on pg 6 and continued on pg 7in the original m/s) that the signal sequence is probably not involved in crust...

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“…It is a 107 amino acid, single polypeptide chain which contains two FDC domains that are cysteine rich (Thompson et al, 1986;Ranganathan et al, 1999). The tertiary structure of SLPI resembles a boomerang shape with the gene located on chromosome 20q12-13.2 (Grutter et al, 1988; Kikuchi et al, 1998).…”

Section: Secretory Leukocyte Protease Inhibitor (Slpi)mentioning

confidence: 99%

“…Murine WAP is recognised as the prototype WFDC protein containing two WAP domains of approximately 50 amino acids which include 8 conserved cysteine residues that form the four-disulfide core (FDC) (Drenth et al, 1980; Piletz et al, 1981). The WFDC signature was initially determined from analysis of a large number of FDC domain cysteine arrangements in a range of species (Ranganathan et al, 1999) ((C1 …”

Section: Introductionmentioning

confidence: 99%

The role of whey acidic protein four-disulfide-core proteins in respiratory health and disease

Small

Doherty

Dougan

et al. 2016

Biological Chemistry

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Members of the whey acidic protein (WAP) or WAP four-disulfide-core (WFDC) family of proteins are a relatively under-explored family of low molecular weight proteins. The two most prominent WFDC proteins, secretory leukocyte protease inhibitor (SLPI) and elafin (or the precursor, trappin-2), have been shown to possess multiple functions including antiprotease, anti-bacterial, anti-viral and anti-inflammatory properties. It is therefore of no surprise that both SLPI and elafin/trappin-2 have been developed as potential therapeutics.Given the abundance of SLPI and elafin/trappin-2 in the human lung, most work in the area of WFDC research has focused on the role of WFDC proteins in protecting the lung from proteolytic attack. In this review, we will outline the current evidence regarding the expanding role of WFDC protein function with a focus on WFDC activity in lung disease as well as emerging data regarding the function of some of the more recently described WFDC proteins.

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The whey acidic protein family: a new signature motif and three-dimensional structure by comparative modeling

Cited by 129 publications

References 32 publications

The evolution of milk secretion and its ancient origins

The evolution of milk secretion and its ancient origins

Crustins: Enigmatic WAP domain-containing antibacterial proteins from crustaceans

The role of whey acidic protein four-disulfide-core proteins in respiratory health and disease

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