title: 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.
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.
authors: Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Epigenomics Translational Program, Center for Individualized Medicine., Mayo Clinic, 200 First Street SW, Guggenheim 10, Rochester, MN, 55905, USA, urrutia.raul@mayo.edu.
authors: Raul
authors: R
authors: Urrutia
authors: Gabriel
authors: G
authors: Velez
authors: Marisa
authors: M
authors: Lin
authors: Gwen
authors: G
authors: Lomberk
authors: Jose Luis
authors: JL
authors: Neira
authors: Juan
authors: J
authors: Iovanna
mesh_terms: D024761:AT-Hook Motifs; D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry*; D017124:Conserved Sequence; D004247:DNA / Q000378:metabolism; D019077:Helix-Turn-Helix Motifs; D006609:High Mobility Group Proteins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D009363:Neoplasm Proteins / Q000737:chemistry*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D006609:High Mobility Group Proteins; D050505:Mutant Proteins; D009363:Neoplasm Proteins; C491643:NUPR1 protein, human