32
Aggregation, Protein
(a)
(b)
(c)
(d)
Fig. 4
Schematic
representation of
domain swapping. (a)
monomeric protein, (b) and (c)
partially unfolded monomers,
(d) domain-swapped dimer.
molecule, thus resulting in an intertwined
dimer or oligomer, as defned by Eisen-
berg and colleagues (Fig. 4). When the
exchange is reciprocated, domain-swapped
dimers are ±ormed. However, i± the ex-
change is not reciprocated but propagated
along multiple polypeptide chains, higher
order assemblies or aggregates may ±orm.
Domain-swapped oligomers are divided
into two types, open and closed. The open
oligomers are linear and have one closed
inter±ace (closed in the monomer) exposed
to the solvent, whereas closed oligomers
are cyclic and do not expose a closed
inter±ace. Eisenberg and coworkers have
defned the structure o± the monomer as
the ‘‘closed monomer’’ and the con±or-
mation o± the polypeptide chain in the
domain-swapped oligomer as the ‘‘open
monomer.’’
The ability o± monomeric proteins to
swap structural elements requires the pres-
ence o± a hinge or linker region that
permits the protein to attain the native
±old with parts o± two polypeptide chains.
In ±act, domain-swapped structures re-
veal regions o± protein structure that are
flexible. Bergdoll and coworkers have sug-
gested that a proline in the linker region,
by rigidi±ying the hinge region in inter-
mediate states, might ±acilitate domain
swapping. Baker and colleagues proposed
that strain in a hairpin loop might pre-
dispose a protein to domain swapping.
The possible role o± 3D domain swapping
in the evolution o± oligomeric proteins
has been discussed in several reviews.
In the past years, the number o± known
domain-swapped proteins has increased
and today about 40 such structures are
solved. One common ±eature o± these pro-
teins is that all the swapped domains
are ±rom either the N-terminus or the
C-terminus o± the polypeptide chain. In
this regard, an interesting example arises
±rom the work o± Eisenberg and his group
on the dimerization o± ribonuclease A.
This protein ±orms two types o± dimers
upon concentration in mild acid. The mi-
nor dimer is ±ormed by swapping o± its
N-terminal
α
-helix with that o± an iden-
tical molecule. The major dimer results
±rom the swapping o± its C-terminal
β
-
strand. RNase A was also reported to ±orm
trimers. On the basis o± the structure o±
the N- and C-terminal swapped dimers,
a model was proposed (Fig. 5). This indi-
cates that two types o± swapping can occur
simultaneously in the same oligomer. Fur-
ther biochemical studies have supported
this model. A less abundant trimer in
which only the C-terminal
β
-strand is
swapped and exhibits a cyclic structure
was also ±ound. RNase represents the
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