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 . 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>) . 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
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 .
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 .
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
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 .
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 .
Green algae Dunaliella salina TTF-1. The membrane associated TTF-1 is
distinctly different in encompassing three, rather than two, transferrin-
like domains .
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.
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