Aggregation, Protein
33
frst protein Found to Form both linear
and
cyclic
domain-swapped
oligomers.
This protein also was described to Form
tetramers. Models based on the structures
oF dimers and trimers were proposed For
these tetramers. Two linear models ex-
hibit both types oF swapping that occur in
one molecule, and a cyclic tetramer shows
the swapping oF the C-terminal
β
-strand
only. A trimeric domain-swapped barnase
was obtained at low pH and high protein
concentration. Crystallographic studies re-
vealed a structure suggesting a probable
Folding intermediate. Domain swapping
was described For the cell cycle regulatory
protein p13suc1, a small protein oF 113
amino acids.
±olding
studies
as
well
as
molecu-
lar
dynamics
simulations
have
shown
that domain swapping occurs in the un-
Folded state. Eisenberg and his colleagues
have proposed a Free energy diagram For
the pathway oF domain swapping. The
Free energy diFFerence between the closed
monomer and domain-swapped oligomer
is small since they share the same struc-
tures except at the hinge loop, but the
energy barrier can be reduced under cer-
tain conditions making domain swapping
more Favorable. Several molecular or envi-
ronmental events may Favor the Formation
oF extended domain-swapped polymers.
Genetic mutations introducing a dele-
tion in the hinge loop can destabilize the
monomeric Form oF a protein. The replace-
ment oF only one amino acid can also Favor
Fig. 5
Domain swapping in
ribonuclease. Ribbon diagram of the
structures of (a) the ribonuclease A
monomer (2.0
˚
A), (b) the N-terminal
swapped dimer (2.1
˚
A), (c) the
C-terminal swapped dimer (1.75
˚
A), (d)
the N- and C-terminal trimer model, and
(e) the cyclic C-terminal swapped trimer
(2.2
˚
A) (reproduced from Liu et al. Prot.
Sci.
11
, 371, 2002 with permission).
(a)
(d)
(e)
(b)
(c)
the polymerization oF the mutated pro-
tein. Three-dimensional domain-swapped
oligomers are expected to be increasingly
Favored as the protein concentration in-
creases. Thus, a metabolic change that
increases the concentration oF a protein
will
Favor
aggregation.
Charge
eFFects,
caused either by mutations or by pH
change or salt concentration, can induce
domain swapping; For example, in RNase
A, a decrease in pH, by protonating the
residues involved in hydrogen bonds and
in salt bridges, lowers the energy barrier
oF the Formation oF the open monomer,
hence inducing domain swapping.
There is great diversity oF swapped do-
mains, with diFFerent sizes and sequences.
They can consist oF entire tertiary do-
mains or smaller structural elements made
oF several residues. No specifc sequence
motiF seems to be involved among the
swapped domains. Three-dimensional do-
main swapping has also been proposed as
a mechanism For amyloid Formation. This
aspect will be discussed in Sect. 4.2.
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