PMID- 30507144
OWN - NLM
STAT- MEDLINE
DCOM- 20190730
LR  - 20231213
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 57
IP  - 51
DP  - 2018 Dec 26
TI  - Structural Basis for Graded Inhibition of CREB:DNA Interactions by Multisite 
      Phosphorylation.
PG  - 6964-6972
LID - 10.1021/acs.biochem.8b01092 [doi]
AB  - Phosphorylation of the kinase inducible domain (KID) of the cyclic AMP response 
      element binding transcription factor (CREB) regulates its function through 
      several mechanisms. Transcriptional activation occurs following phosphorylation 
      at serine 133, but multisite phosphorylation in a neighboring region termed the 
      CK cassette, residues 108-117, results in inhibition of CREB-mediated 
      transcription. A molecular-level understanding of the mechanism of these opposing 
      reactions has been lacking, in part because of the difficulty of preparing 
      multiply phosphorylated CREB in vitro. By substituting a single residue, we have 
      generated an engineered mammalian CREB in which the CK cassette can be 
      phosphorylated in vitro by casein kinases and have characterized its interactions 
      with cyclic AMP response element DNA. Phosphorylation of the CK cassette promotes 
      an intramolecular interaction between the KID domain and the site of DNA binding, 
      the basic region of the C-terminal basic leucine zipper (bZip) domain. 
      Competition between the phosphorylated KID domain and DNA for bZip binding 
      results in a decreased affinity of CREB for DNA. The binding free energy 
      calculated from the dissociation constant is directly proportional to the number 
      of phosphate groups in the CK cassette, indicating that the DNA binding is 
      regulated by a rheostat-like mechanism. The rheostat is modulated by variation of 
      the concentration of cations such as Mg(2+) and by alternative isoforms such as 
      the natural CREB isoform that lacks residues 162-272. Multisite phosphorylation 
      of CREB represents a versatile mechanism by which transcription can be tuned to 
      meet the variable needs of the cell.
FAU - Shnitkind, Sergey
AU  - Shnitkind S
AD  - Department of Integrative Structural and Computational Biology and Skaggs 
      Institute for Chemical Biology , The Scripps Research Institute , 10550 North 
      Torrey Pines Road , La Jolla , California 92037 , United States.
FAU - Martinez-Yamout, Maria A
AU  - Martinez-Yamout MA
AD  - Department of Integrative Structural and Computational Biology and Skaggs 
      Institute for Chemical Biology , The Scripps Research Institute , 10550 North 
      Torrey Pines Road , La Jolla , California 92037 , United States.
FAU - Dyson, H Jane
AU  - Dyson HJ
AUID- ORCID: 0000-0001-6855-3398
AD  - Department of Integrative Structural and Computational Biology and Skaggs 
      Institute for Chemical Biology , The Scripps Research Institute , 10550 North 
      Torrey Pines Road , La Jolla , California 92037 , United States.
FAU - Wright, Peter E
AU  - Wright PE
AUID- ORCID: 0000-0002-1368-0223
AD  - Department of Integrative Structural and Computational Biology and Skaggs 
      Institute for Chemical Biology , The Scripps Research Institute , 10550 North 
      Torrey Pines Road , La Jolla , California 92037 , United States.
LA  - eng
GR  - R01 CA214054/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181213
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Creb1 protein, rat)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 9007-49-2 (DNA)
RN  - I38ZP9992A (Magnesium)
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites
MH  - Cyclic AMP Response Element-Binding Protein/*chemistry/genetics/*metabolism
MH  - DNA/genetics/*metabolism
MH  - Fluorescence Polarization
MH  - Magnesium/pharmacology
MH  - Mutagenesis, Site-Directed
MH  - Nuclear Magnetic Resonance, Biomolecular
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Domains
MH  - Protein Engineering
MH  - Rats
PMC - PMC6474821
MID - NIHMS1001423
EDAT- 2018/12/07 06:00
MHDA- 2019/07/31 06:00
PMCR- 2019/12/26
CRDT- 2018/12/04 06:00
PHST- 2018/12/07 06:00 [pubmed]
PHST- 2019/07/31 06:00 [medline]
PHST- 2018/12/04 06:00 [entrez]
PHST- 2019/12/26 00:00 [pmc-release]
AID - 10.1021/acs.biochem.8b01092 [doi]
PST - ppublish
SO  - Biochemistry. 2018 Dec 26;57(51):6964-6972. doi: 10.1021/acs.biochem.8b01092. 
      Epub 2018 Dec 13.