Insights from the crystal structure of the chicken CREB3 bZIP suggest that members of the CREB3 subfamily transcription factors may be activated in response to oxidative stress

Abstract

cAMP response element binding Protein 3 (CREB3) is an endoplasmic reticulum (ER) membrane‐bound transcription factor, which belongs to the basic leucine zipper (bZIP) superfamily of eukaryotic transcription factors. CREB3 plays a role in the ER‐stress induced unfolded protein response (UPR) and is a multifunctional cellular factor implicated in a number of biological processes including cell proliferation and migration, tumor suppression, and immune‐related gene expression. To gain structural insights into the transcription factor, we determined the crystal structure of the conserved bZIP domain of chicken CREB3 (chCREB3) to a resolution of 3.95 Å. The X‐ray structure provides evidence that chCREB3 can form a stable homodimer. The chCREB3 bZIP has a structured, pre‐formed DNA binding region, even in the absence of DNA, a feature that could potentially enhance both the DNA binding specificity and affinity of chCREB3. Significantly, the homodimeric bZIP possesses an intermolecular disulfide bond that connects equivalent cysteine residues of the parallel helices in the leucine zipper region. This disulfide bond in the hydrophobic core of the bZIP may increase the stability of the homodimer under oxidizing conditions. Moreover, sequence alignment of bZIP sequences from chicken, human, and mouse reveals that only members of the CREB3 subfamily contain this cysteine residue, indicating that it could act as a redox‐sensor. Taken together, these results suggest that the activity of these transcription factors may be redox‐regulated and they may be activated in response to oxidative stress.

CREB3L4 promotes hepatocellular carcinoma progression and decreases sorafenib chemosensitivity by promoting RHEB-mTORC1 signaling pathway

“…CREB3L4, as a member of the basic leucine zipper (bZIP) transcription factor, is reported to involve in many physiological and pathological processes by regulating the transcriptional activity of target genes. 17 It has been recognized as a marker for predicting the prognosis of human cancers because of its high expression in prostate cancer, gastric cancer, and HCC, triggering excessive proliferation of cancer cells. 18 In prostate cancer, CREB3L4 is considered to facilitate the prostatic cancer cell proliferation via interacting with the androgen receptor.…”

The transition state for coupled folding and binding of a disordered DNA binding domain resembles the unbound state

“…The BR mediates DNA recognition and is enriched in positively charged amino acids (43). As shown in a number of X-ray structures, a bZIP assumes a chopstick-like structure of two uninterrupted α-helices grasping the DNA by the major groove (44)(45)(46)(47)(48)(49)(50)(51). Although the bZIP domains have been studied for more than 30 years, there are few details on the mechanism of their binding to DNA.…”