AI Article Synopsis
Article Abstract
Activation of the IκB kinase (IKK) is central to NF-κB signaling. However, the precise activation mechanism by which catalytic IKK subunits gain the ability to induce NF-κB transcriptional activity is not well understood. Here we report a 4 Å x-ray crystal structure of human IKK2 (hIKK2) in its catalytically active conformation. The hIKK2 domain architecture closely resembles that of Xenopus IKK2 (xIKK2). However, whereas inactivated xIKK2 displays a closed dimeric structure, hIKK2 dimers adopt open conformations that permit higher order oligomerization within the crystal. Reversible oligomerization of hIKK2 dimers is observed in solution. Mutagenesis confirms that two of the surfaces that mediate oligomerization within the crystal are also critical for the process of hIKK2 activation in cells. We propose that IKK2 dimers transiently associate with one another through these interaction surfaces to promote trans auto-phosphorylation as part of their mechanism of activation. This structure-based model supports recently published structural data that implicate strand exchange as part of a mechanism for IKK2 activation via trans auto-phosphorylation. Moreover, oligomerization through the interfaces identified in this study and subsequent trans auto-phosphorylation account for the rapid amplification of IKK2 phosphorylation observed even in the absence of any upstream kinase.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678999 | PMC |
| http://dx.doi.org/10.1371/journal.pbio.1001581 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Evidence that the acetyltransferase Tip60 induces the DNA damage response and cell-cycle arrest in neonatal cardiomyocytes.
J Mol Cell Cardiol
June 2021
Department of Cell Biology, Neurobiology and Anatomy and the Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, United States of America. Electronic address:
Tip60, a pan-acetyltransferase encoded by the Kat5 gene, is enriched in the myocardium; however, its function in the heart is unknown. In cancer cells, Tip60 acetylates Atm (Ataxia-telangiectasia mutated), enabling its auto-phosphorylation (pAtm), which activates the DNA damage response (DDR). It was recently reported that activation of pAtm at the time of birth induces the DDR in cardiomyocytes (CMs), resulting in proliferative senescence.
View Article and Find Full Text PDFCaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts.
Cell Death Dis
May 2020
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY, 82071, USA.
Previous studies indicated that Ca/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca-regulated protease μ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion.
View Article and Find Full Text PDFAll-trans retinoic acid attenuates isoproterenol-induced cardiac dysfunction through Crabp1 to dampen CaMKII activation.
Eur J Pharmacol
September 2019
Department of Pharmacology University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address:
Inhibiting Ca/calmodulin-dependent protein kinase II (CaMKII) over activation can decrease detrimental cardiac remodeling that leads to dilated cardiomyopathy, cell death, and heart failure. We previously showed that cellular retinoic acid binding protein 1 (Crabp1) knockout mice (CKO) exhibited a more severe isoproterenol (ISO)-induced heart failure and cardiac remodeling phenotype with elevated CaMKII activity in the heart, suggesting a cardiac-protective function of Crabp1 through modulating CaMKII activity. Here we examine whether the highly selective, endogenous ligand of Crabp1, all-trans retinoic acid (RA), can attenuate ISO-induced cardiac dysfunction.
View Article and Find Full Text PDFSolution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in .
Biochem J
April 2019
Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.
The group A p21-activated kinases (PAKs) exist in an auto-inhibited form until activated by GTPase binding and auto-phosphorylation. In the auto-inhibited form, a regulatory domain binds to the kinase domain (KD) blocking the binding of substrates, and CDC42 or Rac binding to the regulatory domain relieves this auto-inhibition allowing auto-phosphorylation on the KD activation loop. We have determined the crystal structure of the PAK3 catalytic domain and by small angle X-ray scattering, the solution-phase structures of full-length inactive PAK1 and PAK3.
View Article and Find Full Text PDFA conformational sensor based on genetic code expansion reveals an autocatalytic component in EGFR activation.
Nat Commun
September 2018
Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Street 11, 44227, Dortmund, Germany.
Epidermal growth factor receptor (EGFR) activation by growth factors (GFs) relies on dimerization and allosteric activation of its intrinsic kinase activity, resulting in trans-phosphorylation of tyrosines on its C-terminal tail. While structural and biochemical studies identified this EGF-induced allosteric activation, imaging collective EGFR activation in cells and molecular dynamics simulations pointed at additional catalytic EGFR activation mechanisms. To gain more insight into EGFR activation mechanisms in living cells, we develop a Förster resonance energy transfer (FRET)-based conformational EGFR indicator (CONEGI) using genetic code expansion that reports on conformational transitions in the EGFR activation loop.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!