1/2011
vol. 92
abstract:
REVIEW PAPER 3D domain swapping – implications
for conformational disorders and ways of control
BioTechnologia vol. 92(1) C pp. 34-44 C 2011
Online publish date: 2014/10/28
PlumX metrics:
3D Domain swapping is a mechanism of protein aggregation, in which a structural element of a protein fold is replaced
by an identical element from another subunit. Some proteins, for instance RNase A, can assume many domain-
swapped forms, thus undermining the dogma, “one sequence – one structure” in a particularly spectacular
way. Completed in a mutual fashion, it is a mechanism of protein oligomerization. In an open-ended fashion, 3D
domain swapping could be a mechanism of amyloid fibril formation. In another mechanism, possibly operating
together with domain swapping, a specific sequence, such as a glutamine expansion, could form a β-spine of the
fibril in a motif called steric zipper. The first connection between 3D domain swapping and amyloidogenicity was
established in human cystatin C (HCC), the second - in the prion protein (PrP). In both cases, a disulfide bridge
(natural in PrP, engineered in HCC) can be used for redox control of 3D domain swapping and to demonstrate
that it is indeed involved in amyloid fibril formation. HCC has a naturally occurring L68Q mutant with drastically
increased propensity for aggregation. The L68Q mutation occurs at the closed interface, or protein core. Mutations
in other areas, such as the flexible hinge (especially deletions and insertions) can also be used to control
3D domain swapping and aggregation. Paradoxically, 3D domain swapping can also be used by Nature for prevention
of nucleation processes that lead to high-order aggregates or crystals. Such a situation exists in the eye lens,
where despite astronomical concentration of crystallins, the solution remains clear. One of the Nature’s tricks
to achieve polydispersity is to use a palindromic sequence for the swapped domain, thereby frustrating the growth
of aggregates by constantly changing the interaction topology.
keywords:
protein aggregation, mutagenesis, amyloid, fibril, cross-β structure, steric zipper, amylome, ribonuclease
A, human cystatin C, prion protein, crystallins
|
|