scholarly journals Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition

2020 ◽  
Author(s):  
Tom E.H. Ogden ◽  
Ji-Chun Yang ◽  
Marianne Schimpl ◽  
Laura E. Easton ◽  
Elizabeth Underwood ◽  
...  
Keyword(s):  
Dna Binding ◽  
Active Site ◽  
Catalytic Domain ◽  
Parp Activation ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Single Strand Breaks ◽  
Folded Structure ◽  
Early Responder ◽  
Parp 1

ABSTRACTPARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of DNA single-strand breaks by PARP-1’s F1 and F2 domains via a process of further domain assembly to activation of the catalytic domain (CAT); synthesis and attachment of poly(ADP-ribose) (PAR) chains to protein sidechains then signals for assembly of DNA repair components. A key component in transmission of the allosteric signal is the HD subdomain of CAT, which alone bridges between the assembled DNA-binding domains and the active site in the ART subdomain of CAT. Here we present a study of isolated CAT domain from human PARP-1, using NMR-based dynamics experiments to analyse WT apo-protein as well as a set of inhibitor complexes (with veliparib, olaparib, talazoparib and EB-47) and point mutants (L713F, L765A and L765F), together with new crystal structures of the free CAT domain and inhibitor complexes. Variations in both dynamics and structures amongst these species point to a model for full-length PARP-1 activation where first DNA binding and then substrate interaction successively destabilise the folded structure of the HD subdomain to the point where its steric blockade of the active site is released and PAR synthesis can proceed.

scholarly journals Both DNA binding domains of p53 are required for its ultra-rapid recruitment to sites of UV damage

2020 ◽  
Author(s):  
YH. Wang ◽  
T. Ho ◽  
A. Hariharan ◽  
HC. Goh ◽  
MP. Sheetz ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Initial Step ◽  
Uv Laser ◽  
Uv Damage ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Early Responder ◽  
Early Recruitment ◽  
Rapid Binding

Abstractp53 concentrates at DNA damage sites within two seconds upon UV laser micro-irradiation. Structural analysis shows that this very rapid response requires both the DNA binding and C-terminal domains of p53. This early recruitment response is also PARP-dependent. As mutations within the DNA binding domain of p53, that are commonly associated with cancer also inhibit this rapid binding, we suggest that this is an important initial step for p53 function as a tumor suppressor.One Sentence Summaryp53 is an early responder to DNA damage

scholarly journals Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1

2014 ◽  
Vol 289 (31) ◽  
pp. 21605-21616 ◽  
Author(s):  
Shuo Wang ◽  
Miles H. Linde ◽  
Manoj Munde ◽  
Victor D. Carvalho ◽  
W. David Wilson ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Ets Family ◽  
Site Recognition

scholarly journals Protein Kinase A Signaling Pathway Regulates Transcriptional Activity of SAF-1 by Unmasking Its DNA-binding Domains

2003 ◽  
Vol 278 (25) ◽  
pp. 22586-22595 ◽  
Author(s):  
Alpana Ray ◽  
Papiya Ray ◽  
Nicole Guthrie ◽  
Arvind Shakya ◽  
Deepak Kumar ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dna Binding ◽  
Protein Kinase A ◽  
Signaling Pathway ◽  
Transcriptional Activity ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Kinase A

scholarly journals Role of Papillomavirus E1 Initiator Dimerization in DNA Replication

2005 ◽  
Vol 79 (13) ◽  
pp. 8661-8664 ◽  
Author(s):  
Stephen Schuck ◽  
Arne Stenlund
Keyword(s):  
Dna Replication ◽  
Dna Binding ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Severe Effect ◽  
Origin Of Dna Replication ◽  
Initiation Of Dna Replication

ABSTRACT Viral initiator proteins are polypeptides that form oligomeric complexes on the origin of DNA replication (ori). These complexes carry out a multitude of functions related to initiation of DNA replication, and although many of these functions have been characterized biochemically, little is understood about how the complexes are assembled. Here we demonstrate that loss of one particular interaction, the dimerization between E1 DNA binding domains, has a severe effect on DNA replication in vivo but has surprisingly modest effects on most individual biochemical activities in vitro. We conclude that the dimer interaction is primarily required for initial recognition of ori.

scholarly journals Cdc13 N-Terminal Dimerization, DNA Binding, and Telomere Length Regulation

2010 ◽  
Vol 30 (22) ◽  
pp. 5325-5334 ◽  
Author(s):  
Meghan T. Mitchell ◽  
Jasmine S. Smith ◽  
Mark Mason ◽  
Sandy Harper ◽  
David W. Speicher ◽  
...  
Keyword(s):  
Dna Binding ◽  
Telomere Length ◽  
Functional Characterization ◽  
Point Mutations ◽  
Telomeric Dna ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Length Regulation ◽  
Telomere Length Regulation

ABSTRACT The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single-stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres.

Conformational changes in the DNA-binding domains of the ecdysteroid receptor during the formation of a complex with the hsp27 response element

2012 ◽  
Vol 30 (4) ◽  
pp. 379-393 ◽  
Author(s):  
Szymon Pakuła ◽  
Marek Orłowski ◽  
Grzegorz Rymarczyk ◽  
Tomasz Krusiński ◽  
Michał Jakób ◽  
...  
Keyword(s):  
Dna Binding ◽  
Conformational Changes ◽  
Response Element ◽  
Ecdysteroid Receptor ◽  
Dna Binding Domains ◽  
Binding Domains

scholarly journals Differential Gene Regulation by Selective Association of Transcriptional Coactivators and bZIP DNA-Binding Domains

2006 ◽  
Vol 26 (16) ◽  
pp. 5969-5982 ◽  
Author(s):  
Benoit Miotto ◽  
Kevin Struhl
Keyword(s):  
Dna Binding ◽  
Regulation Of Gene Expression ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Transcriptional Coactivators ◽  
Differential Gene Regulation ◽  
Arginine Residues ◽  
Contact Dna ◽  
Bzip Proteins ◽  
Basic Region

ABSTRACT bZIP DNA-binding domains are targets for viral and cellular proteins that function as transcriptional coactivators. Here, we show that MBF1 and the related Chameau and HBO1 histone acetylases interact with distinct subgroups of bZIP proteins, whereas pX does not discriminate. Selectivity of Chameau and MBF1 for bZIP proteins is mediated by residues in the basic region that lie on the opposite surface from residues that contact DNA. Chameau functions as a specific coactivator for the AP-1 class of bZIP proteins via two arginine residues. A conserved glutamic acid/glutamine in the linker region underlies MBF1 specificity for a subgroup of bZIP factors. Chameau and MBF1 cannot synergistically coactivate transcription due to competitive interactions with the basic region, but either protein can synergistically coactivate with pX. Analysis of Jun derivatives that selectively interact with these coactivators reveals that MBF1 is crucial for the response to oxidative stress, whereas Chameau is important for the response to chemical and osmotic stress. Thus, the bZIP domain mediates selective interactions with coactivators and hence differential regulation of gene expression.

Sign in / Sign up

Export Citation Format

Share Document