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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. J Mol Model 2014 Aug;20(8):2357 PMID: 25056123 PMCID: PMC4139591

Pubmed ID

25056123

DOI

10.1007/s00894-014-2357-7

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-groove-binding proteins that share structural features with, yet are distinct from, helix-loop-helix AT-hook-containing HMG proteins. 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.

Author List

Urrutia R, Velez G, Lin M, Lomberk G, Neira JL, Iovanna J

Authors

Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84904525832   7 Citations

MESH terms used to index this publication - Major topics in bold

AT-Hook Motifs
Amino Acid Sequence
Basic Helix-Loop-Helix Transcription Factors
Conserved Sequence
DNA
Helix-Turn-Helix Motifs
High Mobility Group Proteins
Humans
Models, Molecular
Molecular Sequence Data
Mutant Proteins
Neoplasm Proteins
Nucleic Acid Conformation
Protein Binding
Protein Processing, Post-Translational
Protein Structure, Tertiary
Transcription, Genetic
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad