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PROSITE documentation PDOC00182 [for PROSITE entry PS00207]

Transferrin-like domain signatures and profile





Description

The transferrin family is a group of glycosylated proteins found in both vertebrates and invertebrates. Included in this group are molecules known to bind iron, including serotransferrin, ovotransferrin, lactotransferrin, and melanotransferrin (MTF). Additional members of this family include inhibitor of carbonic anhydrase (ICA; mammals), major yolk protein (sea urchins), saxiphilin (frog), pacifastin (crayfish), and TTF-1 (algae). Most family members contain two transferrin-like domains of around 340 amino acids, the result of an ancient duplication event [1]. Each of the duplicated domains can be further divided into two subdomains that form a cleft inside of which the iron atom is bound in iron-transporting transferrin (see <PDB:1LFH>) [2]. The iron-coordinating residues consist of an aspartic acid, two tyrosines and a histidine, as well as an arginine that coordinates a requisite anion. In addition to iron and anion liganding residues, the transferrin-like domain contains conserved cysteine residues involved in disulfide bond formation.

Some proteins known to contain a transferrin-like domain are listed below:

  • Mammalian blood serotransferrin (siderophilin). It functions to deliver iron to cells via a receptor-mediated endocytic process as well to remove toxic free iron from the blood and to provide an anti-bacterial, low-iron environment.
  • Mammalian milk lactotransferrin (lactoferrin). It has antimicrobial activity and contributes to innate immunity by limiting the availability of iron to pathogenic organisms. In addition, lactoferrin appears to be a serine protease of the peptidase S60 family [E1] with an active site that may consist of a Ser-Lys catalytic dyad. Lactoferrin cleaves the putative Haemophilus influenzae colonization factors IgA1 protease and Hap adhesin at homologous arginine-rich sequences [3].
  • Vertebrate egg white ovotransferrin (conalbumin). Its major function is thought to be keeping the iron concentration low in bodily fluids to prevent invading bacteria from acquiring iron.
  • Mammalian membrane-associated melanotransferrin. It was first identified in human skin cells but now is known to be expressed across a broad range of tissue types, and is of unknown function. It has only a single functional iron binding site located in its N-terminal domain.
  • Porcine inhibitor of carbonic anhydrase (ICA). It specifically binds and inhibits carbonic anhydrase 2 with nanomolar affinity but does not bind iron with high affinity [4].
  • Bull frog saxiphilin, a plasma protein that binds saxitoxin (STX), a causative agent of paralytic shellfish poisoning. STX binds to the C-terminal transferrin-like domain of saxiphilin. The N-terminal transferrin-like domain includes an insert that represent two tandem thyroglobulin domains. Unlike transferrins, saxiphilin does not bind iron [5].
  • Sea urchin toposome or major yolk protein (MYP), a modified calcium- binding, iron-less transferrin essential for cell adhesion and development. The protein lacks most of the five iron-binding amino acids D, Y, R, Y, and H present at specific positions in iron-transporting transferrins, which is consistent with the Ca(2+)-binding function of the toposome in cell adhesion rather than transport. The toposome polypeptide contains an insertion of some 280 amino acids in the second transferrin-like [6].
  • Crayfish pacifastin, an iron-binding serine proteinase inhibitor. This protein is a heterodimeric protein, consisting of one proteinase inhibitory light chain, and one heavy chain related to transferrins. The pacifastin heavy chain contains three transferrin-like domains, two of which seem to be active for iron binding [7].
  • Green algae Dunaliella salina TTF-1. The membrane associated TTF-1 is distinctly different in encompassing three, rather than two, transferrin- like domains [8].

We have developed three different signature patterns for iron-binding transferrin-like domains. Each of them is centered on one of the iron-binding residue, respectively the two tyrosines and the histidine. We also developed a profile which covers the entire transferrin-like domain.

Last update:

February 2009 / Text revised.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

TRANSFERRIN_LIKE_3, PS00207; Transferrin-like domain signature 3  (PATTERN)

TRANSFERRIN_LIKE_4, PS51408; Transferrin-like domain profile  (MATRIX)

TRANSFERRIN_LIKE_1, PS00205; Transferrin-like domain signature 1  (PATTERN)

TRANSFERRIN_LIKE_2, PS00206; Transferrin-like domain signature 2  (PATTERN)


References

1AuthorsLambert L.A. Perri H. Meehan T.J.
TitleEvolution of duplications in the transferrin family of proteins.
SourceComp. Biochem. Physiol. 140B:11-25(2005).
PubMed ID15621505
DOI10.1016/j.cbpc.2004.09.012

2AuthorsAnderson B.F. Baker H.M. Norris G.E. Rice D.W. Baker E.N.
TitleStructure of human lactoferrin: crystallographic structure analysis and refinement at 2.8 A resolution.
SourceJ. Mol. Biol. 209:711-734(1989).
PubMed ID2585506

3AuthorsHendrixson D.R. Qiu J. Shewry S.C. Fink D.L. Petty S. Baker E.N. Plaut A.G. St. Geme J.W. III
TitleHuman milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites.
SourceMol. Microbiol. 47:607-617(2003).
PubMed ID12535064

4AuthorsWuebbens M.W. Roush E.D. Decastro C.M. Fierke C.A.
TitleCloning, sequencing, and recombinant expression of the porcine inhibitor of carbonic anhydrase: a novel member of the transferrin family.
SourceBiochemistry 36:4327-4336(1997).
PubMed ID9100029
DOI10.1021/bi9627424

5AuthorsKrishnan G. Morabito M.A. Moczydlowski E.
TitleExpression and characterization of Flag-epitope- and hexahistidine-tagged derivatives of saxiphilin for use in detection and assay of saxitoxin.
SourceToxicon 39:291-301(2001).
PubMed ID10978747

6AuthorsNoll H. Alcedo J. Daube M. Frei E. Schiltz E. Hunt J. Humphries T. Matranga V. Hochstrasser M. Aebersold R. Lee H. Noll M.
TitleThe toposome, essential for sea urchin cell adhesion and development, is a modified iron-less calcium-binding transferrin.
SourceDev. Biol. 310:54-70(2007).
PubMed ID17707791
DOI10.1016/j.ydbio.2007.07.016

7AuthorsLiang Z. Sottrup-Jensen L. Aspan A. Hall M. Soederhaell K.
TitlePacifastin, a novel 155-kDa heterodimeric proteinase inhibitor containing a unique transferrin chain.
SourceProc. Natl. Acad. Sci. U.S.A. 94:6682-6687(1997).
PubMed ID9192625

8AuthorsFisher M. Gokhman I. Pick U. Zamir A.
TitleA structurally novel transferrin-like protein accumulates in the plasma membrane of the unicellular green alga Dunaliella salina grown in high salinities.
SourceJ. Biol. Chem. 272:1565-1570(1997).
PubMed ID8999829

E1Titlehttps://www.ebi.ac.uk/merops/cgi-bin/famsum?family=s60



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