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Impact of Mutations on NPAC Structural Dynamics: Mechanistic Insights from MD Simulations
journal contribution
posted on 2019-08-21, 13:54 authored by Marco Montefiori, Simona Pilotto, Chiara Marabelli, Elisabetta Moroni, Mariarosaria Ferraro, Stefano A. Serapian, Andrea Mattevi, Giorgio ColomboNPAC
is a cytokine-like nuclear factor involved in chromatin modification
and regulation of gene expression. In humans, the C-terminal domain
of NPAC has the conserved structure of the β-hydroxyacid dehydrogenases
(β-HAD) protein superfamily, which forms a stable tetrameric
core scaffold for demethylase enzymes and organizes multiple sites
for chromatin interactions. In spite of the close structural resemblance
to other β-HAD family members, the human NPAC dehydrogenase
domain lacks a highly conserved catalytic lysine, substituted by a
methionine. The reintroduction of the catalytic lysine by M437 K mutation
results in a significant decrease of stability of the tetramer. Here,
we have computationally investigated the molecular determinants of
the functional differences between methionine and lysine-containing
NPAC proteins. We find that the single mutation can determine strong
consequences in terms of dynamics, stability, and ultimately ability
to assemble in supramolecular complexes: the higher stability and
lower flexibility of the methionine variant structurally preorganizes
the monomer for tetramerization, whereas lysine increases flexibility
and favors conformations that, while catalytically active, are not
optimal for tetrameric assembly. We combine structure-dynamics analysis
to an evolutionary study of NPAC sequences, showing that the methionine
mutation occurs in a specifically flexible region of the lysine-containing
protein, flanked by two domains that concentrate most of the stabilizing
interactions. In our model, such separation of stability nuclei and
flexible regions appears to favor the functional innovability of the
protein.
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Keywords
NPAC dehydrogenase domainmethionine mutationsupramolecular complexesstructure-dynamics analysisM 437 K mutation resultsdemethylase enzymesstability nucleiC-terminal domainlysine-containing NPAC proteinslysine-containing proteintetrameric assemblyNPAC Structural Dynamicsgene expressionMD Simulations NPACMechanistic Insightsprotein superfamilylysine increases flexibilityNPAC sequenceschromatin modificationtetrameric core scaffoldmethionine variantchromatin interactionsfamily members
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