10.1021/acs.jpcb.6b03968.s001
Nahren Manuel Mascarenhas
Nahren Manuel
Mascarenhas
Shachi Gosavi
Shachi
Gosavi
Protein Domain-Swapping Can Be a Consequence of Functional
Residues
American Chemical Society
2016
protease
scMn
simulation
residue
monellin
protein structure
formation
Functional Residues Monomer topology
variant
region
2016-06-22 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Protein_Domain-Swapping_Can_Be_a_Consequence_of_Functional_Residues/3484097
Monomer topology
has been implicated in domain-swapping, a potential
first step on the route to disease-causing protein aggregation. Despite
having the same topology (β1-α1-β2-β3-β4-β5),
the cysteine protease inhibitor stefin-B domain swaps more readily
than a single-chain variant of the heterodimeric sweet protein monellin
(scMn). Here, we computationally study the folding of stefin-B and
scMn in order to understand the molecular basis for the difference
in their domain-swapping propensities. In agreement with experiments,
our structure-based simulations show that scMn folds cooperatively
without the population of an intermediate while stefin-B populates
an equilibrium intermediate state. Since the simulation intermediate
has only one domain structured (β3-β4-β5), it can
directly lead to domain-swapping. Using computational variants of
stefin-B, we show that the population of this intermediate is caused
by regions of stefin-B that have been implicated in protease inhibition.
We also find that the protease-binding regions are located on two
structural elements and localized in space. In contrast, the residues
that contribute to the sweetness of monellin are not localized to
a few structural elements but are distributed over the protein fold.
We conclude that the distributed functional residues of monellin do
not induce large local perturbations in the protein structure, eliminating
the formation of folding intermediates and in turn domain-swapping.
On the other hand, the localized protease-binding regions of stefin-B
promote the formation of a folding intermediate which can lead to
domain-swapping. Thus, domain-swapping can be a direct consequence
of the constraints that function imposes on the protein structure.