TY - JOUR
T1 - 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
AU - Urrutia, Raul
AU - Velez, Gabriel
AU - Lin, Marisa
AU - Lomberk, Gwen
AU - Neira, Jose Luis
AU - Iovanna, Juan
N1 - Funding Information:
This work was supported by funding from the National Institutes of Health (grant DK52913 to RU), a Career Development Award from the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701 to GL), the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567 to GL), the Spanish Ministerio de Ciencia e Innovacion (MCINN) [CTQ2011-24393 to JLN, CSD2008-00005 to JLN], intramural BIFI 2011 projects (to JLN), Generalitat Valenciana [Prometeo 018/2013] (to JLN), and by La Ligue Contre le Cancer, INCa, Canceropole PACA, and INSERM (to JLI).
PY - 2014/8
Y1 - 2014/8
N2 - 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.
AB - 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.
KW - DNA-binding proteins
KW - High Mobility Group (HMG)
KW - Molecular dynamics
KW - NUPR1
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U2 - 10.1007/s00894-014-2357-7
DO - 10.1007/s00894-014-2357-7
M3 - Article
C2 - 25056123
AN - SCOPUS:84904525832
SN - 1610-2940
VL - 20
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
IS - 8
M1 - 2357
ER -