sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / motor learning / negative regulation of dendritic spine morphogenesis / regulation of ubiquitin-dependent protein catabolic process / prostate gland growth / HECT-type E3 ubiquitin transferase / regulation of proteolysis / activation of GTPase activity ...sperm entry / positive regulation of Golgi lumen acidification / symbiont-mediated suppression of host transcription / motor learning / negative regulation of dendritic spine morphogenesis / regulation of ubiquitin-dependent protein catabolic process / prostate gland growth / HECT-type E3 ubiquitin transferase / regulation of proteolysis / activation of GTPase activity / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / RUNX3 regulates CDKN1A transcription / germ cell nucleus / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / negative regulation of neuroblast proliferation / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / B cell lineage commitment / thymocyte apoptotic process / positive regulation of cardiac muscle cell apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / androgen receptor signaling pathway / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / locomotory exploration behavior / progesterone receptor signaling pathway / Zygotic genome activation (ZGA) / necroptotic process / negative regulation of telomere maintenance via telomerase / rRNA transcription / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / SUMOylation of transcription factors / carbohydrate transmembrane transporter activity / intrinsic apoptotic signaling pathway by p53 class mediator / neuroblast proliferation / general transcription initiation factor binding / cellular response to actinomycin D / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / response to X-ray / replicative senescence / chromosome organization / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to UV-C / gastrulation / response to inorganic substance / hematopoietic stem cell differentiation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of RNA polymerase II transcription preinitiation complex assembly / negative regulation of reactive oxygen species metabolic process / protein K48-linked ubiquitination / MDM2/MDM4 family protein binding / embryonic organ development / glial cell proliferation / cellular response to glucose starvation / protein autoubiquitination Similarity search - Function
Journal: Nat Commun / Year: 2024 Title: Structure of the p53 degradation complex from HPV16. Authors: John C K Wang / Hannah T Baddock / Amirhossein Mafi / Ian T Foe / Matthew Bratkowski / Ting-Yu Lin / Zena D Jensvold / Magdalena Preciado López / David Stokoe / Dan Eaton / Qi Hao / Aaron H Nile / Abstract: Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3- ...Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated.
Name: Maltose/maltodextrin-binding periplasmic protein,Protein E6 type: protein_or_peptide / ID: 1 Details: The cysteine to serine mutations are in the protein E6 portion of the chimeric construct.,The cysteine to serine mutations are in the protein E6 portion of the chimeric construct. Number of copies: 1 / Enantiomer: LEVO
Name: ZINC ION / type: ligand / ID: 4 / Number of copies: 3 / Formula: ZN
Molecular weight
Theoretical: 65.409 Da
-
Experimental details
-
Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
-
Sample preparation
Concentration
2.15 mg/mL
Buffer
pH: 7 Component:
Concentration
Formula
Name
50.0 mM
C4H11NO3
Tris
150.0 mM
NaClSodium chloride
Sodium Chloride
5.0 mM
C4H10O2S2
DTT
0.01 Percent
C32H58N2O8S
CHAPSOCHAPS detergent
Grid
Model: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 30 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
Vitrification
Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
-
Electron microscopy
Microscope
FEI TITAN KRIOS
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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