Breast
7/24/2010
. Mol Cell Biol. 2010
Jan;30(1):220-30. Department of Internal Medicine,
University of Texas Medical Branch, Galveston, Texas 77555, USA. Intrinsically disordered (ID)
regions are disproportionately higher in cell signaling proteins and are
predicted to have much larger frequency of phosphorylation sites than
ordered regions, suggesting an important role in their regulatory capacity.
In this study, we show that AF1, an ID activation domain of the
glucocorticoid receptor (GR), adopts a functionally folded conformation due
to its site-specific phosphorylation by p38 mitogen-activated protein
kinase, which is involved in apoptotic and gene-inductive events initiated
by the GR. Further, we show that site-specific phosphorylation-induced
secondary and tertiary structure formation specifically facilitates AF1's
interaction with critical coregulatory proteins and subsequently its
transcriptional activity. These data demonstrate a mechanism through which
ID activation domain of the steroid receptors and other similar
transcription factors may adopt a functionally active conformation under
physiological conditions. PMID:
19841061 [PubMed Arch Biochem Biophys.
2010 Apr 15;496(2):140-5. Epub 2010 Feb 25. Department of Basic Sciences, The
Commonwealth Medical College, Scranton, PA 18510, USA. rkumar@tcmedc.org Despite their importance in gene
regulation, the exact mechanisms of glucocorticoid receptor's (GR's)
N-terminal activation function region, AF1, which exists in an intrinsically
disordered (ID) conformation remains largely unknown. For its interaction
with critical coregulatory proteins, AF1 must be malleable and capable of
presenting varied interaction surfaces. We hypothesize that various
confluences of effects, including intra-molecular signaling between the AF1
and the GR DNA-binding domain (DBD) cause functional structure to form in
AF1. In this study, we tested the effect of the amino acid sequences
surrounding AF1 on the propensity of AF1 to gain structure when connected
to DBD. Removal of amino acids between AF1 and DBD results in the formation
of more ordered conformation in AF1. In addition, sequences flanking the
AF1 may play an inhibitory role in AF1 activity. These results suggest a
mechanism as to why certain GR isoforms with truncated N-terminal domains
show altered transcriptional activity. 2010 Elsevier Inc. All rights
reserved. PMID:
20188692 [
Site-specific phosphorylation
induces functionally active conformation in the intrinsically disordered
N-terminal activation function (AF1) domain of the glucocorticoid receptor.
Abstract
Influence of flanking sequences
on signaling between the activation function AF1 and DNA-binding domain of
the glucocorticoid receptor.
Abstract