Role of Structural and Dynamical Plasticity in Sin3:
The Free PAH2 Domain is a Folded Module in mSin3B
The co-repressor Sin3 is the essential scaffold
protein of the Sin3/HDAC co-repressor complex, which is
recruited to the DNA by a diverse group of transcriptional
repressors, targeting genes involved in the regulation of
the cell cycle, proliferation and differentiation. Sin3
contains four repeats commonly denoted as Paired
Amphipathic Helix (PAH1-4) domains that provide the
principal interaction surface for various repressors. Here,
we present the first structure of the free state of the
PAH2 domain and discuss its implications for interaction
with the repressors. The unbound conformation is highly
similar to the conformation found when bound to either the
Mad1 or HBP1 repressor, suggesting that the PAH2 domain
serves as a template that guides proper folding of the
unstructured repressor. The free PAH2 domain shows μs-ms
conformational exchange between the folded, major state and
a partially unfolded, minor state. Upon complex formation,
we observe a significant decrease in fast time scale
flexibility of local regions of the protein, correlated
with the formation of intermolecular contacts, and an
overall decrease in the slow time scale conformational
exchange. On the basis of our data and using a multiple
sequence alignment of all PAH domains, we suggest that the
PAH1, PAH2 and PAH3 domains form pre-folded binding modules
in full length Sin3 like ‘beads-on-a-string’
and act as folding templates for the interaction domains of
their targets.
PDB code 2F05. (
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■ Van Ingen, H., Baltussen, M.A.H, Aelen, J. &
Vuister, G.W. (2006) “Role of Structural and
Dynamical Plasticity in Sin3: The Free PAH2 Domain is a
Folded Module in mSin3B”,
J. Mol. Biol.
358, 485-497.
