PXD043233

PXD043233 is an original dataset announced via ProteomeXchange.

Title	Fuzzy interactions between the auto-phosphorylated C-terminus and the kinase domain of CK1δ inhibits activation of TAp63α
Description	The p53 family member TAp63α plays an important role in maintaining the genetic integrity in oocytes. DNA damage, in particular DNA double strand breaks, lead to the transformation of the inhibited, only dimeric conformation into the active tetrameric one that results in the initiation of an apoptotic program. Activation requires phosphorylation by the kinase CK1 which phosphorylates TAp63α at four positions. The third phosphorylation event is the decisive step that transforms TAp63α into the active state. This third phosphorylation, however, is ~20 times slower than the first two phosphorylation events. This difference in the phosphorylation kinetics constitutes a safety mechanism that allows oocytes with a low degree of DNA damage to survive. So far these kinetic investigations of the phosphorylation steps have been performed with the isolated CK1 kinase domain. However, all CK1 enzymes contain C-terminal extensions that become auto-phosphorylated and inhibit the activity of the kinase. Here we have investigated the effect of auto-phosphorylation of the C-terminus in the kinase CK1δ and show that it slows down phosphorylation of the first two sites in TAp63α but basically inhibits the phosphorylation of the third site. We have identified up to ten auto-phosphorylation sites in the CK1δ C-terminal domain and show that all of them interact with the kinase domain in a “fuzzy” way in which not a single site is particularly important. Through mutation analysis we further show that hydrophobic amino acids following the phosphorylation site are important for a substrate to be able to successfully compete with the auto-inhibitory effect of the C-terminal domain. This auto-phosphorylation adds a new layer to the regulation of apoptosis in oocytes.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:05:05.900.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christian Münch
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-06-23 05:06:12	ID requested
1	2023-10-06 05:27:16	announced
2	2023-11-14 09:05:51	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:05:06	announced	2024-10-22: Updated project metadata.

Lambert M, Gebel J, Trejtnar C, Wesch N, Bozkurt S, Adrian-Allgood M, L, ö, hr F, M, ü, nch C, D, ö, tsch V, . Sci Rep, 13(1):16423(2023) [pubmed]

10.1038/s41598-023-43515-x;

submitter keyword: CK1, ovarian reserve, p53 family, quality control, phosphorylation,p63, tetramerization, DNA damage, premature ovarian insufficiency

Christian Münch
contact affiliation	Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany Frankfurt Cancer Institute, Frankfurt am Main, Germany Cardio-Pulmonary Institute, Frankfurt am Main, Germany
contact email	bozkurt@med.uni-frankfurt.de
lab head
Christian Münch
contact affiliation	Goethe University Frankfurt
contact email	ch.muench@em.uni-frankfurt.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043233
     1. Label: PRIDE project
     2. Name: Fuzzy interactions between the auto-phosphorylated C-terminus and the kinase domain of CK1δ inhibits activation of TAp63α