Evidence supporting the existence of a NUPR1-like family of helix-loop-helix chromatin proteins related to, yet distinct from, AT hook-containing HMG proteins

Raul Urrutia, Gabriel Velez, Marisa Lin, Gwen Lomberk, Jose Luis Neira, Juan Iovanna

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

NUPR1, a small chromatin protein, plays a critical role in cancer development, progression, and resistance to therapy. Here, using a combination of structural bioinformatics and molecular modeling methods, we report several novel findings that enhance our understanding of the biochemical function of this protein. We find that NUPR1 has been conserved throughout evolution, and over time it has undergone duplications and transpositions to form other transcriptional regulators. Using threading, homology-based molecular modeling, molecular mechanics calculations, and molecular dynamics simulations, we generated structural models for four of these proteins: NUPR1a, NUPR1b, NUPR2, and the NUPR-like domain of GTF2-I. Comparative analyses of these models combined with extensive linear motif identification reveal that these four proteins, though similar in their propensities for folding, differ in size, surface changes, and sites amenable for posttranslational modification. Lastly, taking NUPR1a as the paradigm for this family, we built models of a NUPR-DNA complex. Additional structural comparisons revealed that NUPR1 defines a new family of small-groovebinding proteins that share structural features with, yet are distinct from, helix-loop-helix AT-hook-containing HMGproteins. These models and inferences should lead to a better understanding of the function of this group of chromatin proteins, which play a critical role in the development of human malignant diseases.

Original languageEnglish (US)
Article number2357
JournalJournal of Molecular Modeling
Volume20
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • DNA-binding proteins
  • High Mobility Group (HMG)
  • Molecular dynamics
  • NUPR1

ASJC Scopus subject areas

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry

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