DNA phosphate crowding correlates with protein cationic side chain density and helical curvature in protein/DNA crystal structures

Grant, Bryce N.; Dourlain, Elizabeth; Araneda, Jayme N.; Throneberry, Madison L.; McFail-Isom, Lori

doi:10.1093/nar/gkt492

Cited by 7 publications

(4 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structural distortions induced by DNA kinks or bends generate a local environment of phosphate crowding that is suitable for protein cationic interactions. 68 These observations suggests a model in which CAP may recognize the curvature of DNA at medium distance via electrostatic interactions, whereas the final shaping would be mediated by close contacts and desolvation, which is in agreement with previous atomistic MD simulations. 69 ■ CONCLUSIONS…”

supporting

confidence: 90%

Exploring LacI–DNA Dynamics by Multiscale Simulations Using the SIRAH Force Field

Machado

Pantano

2015

J. Chem. Theory Comput.

View full text Add to dashboard Cite

The lac repressor protein (LacI) together with its target regulatory sequence are a common model for studying DNA looping and its implications on transcriptional control in bacteria. Owing to the molecular size of this system, standard all-atom (AA) simulations are prohibitive for achieving relevant biological time scales. As an alternative, multiscale models, which combine AA descriptions at particular regions with coarse-grained (CG) representations of the remaining components, were used to address this computational challenge while preserving the relevant details of the system. In this work, we implement a new multiscale approach based on the SIRAH force field to gain deeper insights into the dynamics of the LacI-DNA system. Our methodology allows for a dual resolution treatment of the solute and solvent, explicitly representing the protein, DNA, and solvent environment without compromising the AA region. Starting from the P1 loop configuration in an undertwisted conformation, we were able to observe the transition to the more stable overtwisted state. Additionally, a detailed characterization of the conformational space sampled by the DNA loop was done. In agreement with experimental and theoretical evidence, we observed the transient formation of kinks at the loop, which were stabilized by the presence of counterions at the minor groove. We also show that the loop's intrinsic flexibility can account for reported FRET measurements and bent conformations required to bind the CAP transcription factor.

show abstract

supporting

confidence: 90%

Exploring LacI–DNA Dynamics by Multiscale Simulations Using the SIRAH Force Field

Machado

Pantano

2015

J. Chem. Theory Comput.

View full text Add to dashboard Cite

show abstract

“…Our bioinformatic approach indicates that the substitution of the arginine for glutamine in the p.Arg396Gln mutation could impair binding to DNA. Several studies propose that cationic regions of proteins that contain arginine or lysine mediate the nonspecific interaction between the protein and the negatively charged phosphate group of DNA backbone (27). Accordingly, Arg 396 would stabilize the non-sequence-specific binding to DNA, mediating electrostatic interactions with the phosphate group.…”

Section: Discussionmentioning

confidence: 99%

GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

Cortés-Lavaud

Landecho

Maicas

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Germline GATA2 mutations have been identified as the cause of familial syndromes with immunodeficiency and predisposition to myeloid malignancies. GATA2 mutations appear to cause loss of function of the mutated allele leading to haploinsufficiency; however, this postulate has not been experimentally validated as the basis of these syndromes. We hypothesized that mutations that are translated into abnormal proteins could affect the transcription of GATA2, triggering GATA2 deficiency. Chromatin immunoprecipitation and luciferase assays showed that the human GATA2 protein activates its own transcription through a specific region located at −2.4 kb, whereas the p.Thr354Met, p.Thr355del, and p.Arg396Gln germline mutations impair GATA2 promoter activation. Accordingly, GATA2 expression was decreased to ∼58% in a patient with p.Arg396Gln, compared with controls. p.Arg396Gln is the second most common mutation in these syndromes, and no previous functional analyses have been performed. We therefore analyzed p.Arg396Gln. Our data show that p.Arg396Gln is a loss-of-function mutation affecting DNA-binding ability and, as a consequence, it fails to maintain the immature characteristics of hematopoietic stem and progenitor cells, which could result in defects in this cell compartment. In conclusion, we show that human GATA2 binds to its own promoter, activating its transcription, and that the aforementioned mutations impair the transcription of GATA2. Our results indicate that they can affect other GATA2 target genes, which could partially explain the variability of symptoms in these diseases. Moreover, we show that p.Arg396Gln is a loss-of-function mutation, which is unable to retain the progenitor phenotype in cells where it is expressed.

show abstract

“…Positively charged lysines can help mediate non-specific interactions of proteins with the negatively charged phosphate backbone of DNA ( 58 – 60 ), and the positive charge of the lysine patch within the viral genome-binding domain of LANA is required for binding to the acidic patch of BET proteins BRD2 and BRD4 ( 61 , 62 ). However, our arginine substitution data ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Triple lysine and nucleosome-binding motifs of the viral IE19 protein are required for human cytomegalovirus S-phase infections

Maliano,

Yetming,

Kalejta

2024

mBio

View full text Add to dashboard Cite

Herpesvirus genomes are maintained as extrachromosomal plasmids within the nuclei of infected cells. Some herpesviruses persist within dividing cells, putting the viral genome at risk of being lost to the cytoplasm during mitosis because karyokinesis (nuclear division) requires nuclear envelope breakdown. Oncogenic herpesviruses (and papillomaviruses) avoid genome loss during mitosis by tethering their genomes to cellular chromosomes, thereby ensuring viral genome uptake into newly formed nuclei. These viruses use viral proteins with DNA- and chromatin-binding capabilities to physically link viral and cellular genomes together in a process called tethering. The known viral tethering proteins of human papillomavirus (E2), Epstein-Barr virus (EBNA1), and Kaposi’s sarcoma-associated herpesvirus (LANA) each contain two independent domains required for genome tethering, one that binds sequence specifically to the viral genome and another that binds to cellular chromatin. This latter domain is called a chromatin tethering domain (CTD). The human cytomegalovirus UL123 gene encodes a CTD that is required for the virus to productively infect dividing fibroblast cells within the S phase of the cell cycle, presumably by tethering the viral genome to cellular chromosomes during mitosis. The CTD-containing UL123 gene product that supports S-phase infections is the IE19 protein. Here, we define two motifs in IE19 required for S-phase infections: an N-terminal triple lysine motif and a C-terminal nucleosome-binding motif within the CTD. IMPORTANCE The IE19 protein encoded by human cytomegalovirus (HCMV) is required for S-phase infection of dividing cells, likely because it tethers the viral genome to cellular chromosomes, thereby allowing them to survive mitosis. The mechanism through which IE19 tethers viral genomes to cellular chromosomes is not understood. For human papillomavirus, Epstein-Barr virus, and Kaposi’s sarcoma-associated herpesvirus, viral genome tethering is required for persistence (latency) and pathogenesis (oncogenesis). Like these viruses, HCMV also achieves latency, and it modulates the properties of glioblastoma multiforme tumors. Therefore, defining the mechanism through which IE19 tethers viral genomes to cellular chromosomes may help us understand, and ultimately combat or control, HCMV latency and oncomodulation.

show abstract

DNA phosphate crowding correlates with protein cationic side chain density and helical curvature in protein/DNA crystal structures

Cited by 7 publications

References 35 publications

Exploring LacI–DNA Dynamics by Multiscale Simulations Using the SIRAH Force Field

Exploring LacI–DNA Dynamics by Multiscale Simulations Using the SIRAH Force Field

GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

Triple lysine and nucleosome-binding motifs of the viral IE19 protein are required for human cytomegalovirus S-phase infections

Contact Info

Product

Resources

About