Dataset Information

Integrative Threading of the DNA-PKcs Disordered Region with Crosslinking Restraints

ABSTRACT: Integrative structure modelling was applied to understand how auto-phosphorylation of the ABCDE cluster in DNA-PKcs can occur. We used crosslinking restraints to assign sequence to structurally unassigned helices in DNA-PKcs s in the largely disordered region containing the ABCDE cluster. Our final model positions the ABCDE cluster at the end of the second helices, suggesting that phosphorylation occurs through trans-auto-phosphorylation, or through a large conformational change in the disordered region for cis-auto-phosphorylation.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Morgan Hepburn

LAB HEAD: David C. Schriemer

PROVIDER: PXD016639 | Pride | 2019-12-10

REPOSITORIES: Pride

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SSEThread: Integrative threading of the DNA-PKcs sequence based on data from chemical cross-linking and hydrogen deuterium exchange.

Saltzberg Daniel J DJ Hepburn Morgan M Pilla Kala Bharath KB Schriemer David C DC Lees-Miller Susan P SP Blundell Tom L TL Sali Andrej A

Progress in biophysics and molecular biology 20190927

X-ray crystallography and electron microscopy maps resolved to 3-8 Å are generally sufficient for tracing the path of the polypeptide chain in space, while often insufficient for unambiguously registering the sequence on the path (i.e., threading). Frequently, however, additional information is available from other biophysical experiments, physical principles, statistical analyses, and other prior models. Here, we formulate an integrative approach for sequence assignment to a partial backbone mo ...[more]

PMID: 31570166

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Project description:Objective Estrogen-related-receptor α (ERRα) plays a critical role in the transcriptional regulation of cellular bioenergetics and metabolism, and perturbations in its activity have been associated with metabolic diseases. While several coactivators and corepressors of ERRα have been identified to date, a knowledge gap remains in understanding the extent to which ERRα cooperates with coregulators in the control of gene expression. Herein, we mapped the primary chromatin-bound ERRα interactome in mouse liver. Methods RIME (Rapid Immuno-precipitation Mass spectrometry of Endogenous proteins) analysis using mouse liver samples from two circadian time points was used to catalog ERRα-interacting proteins on chromatin. The genomic crosstalk between ERRα and its identified cofactors in the transcriptional control of precise gene programs was explored through cross-examination of genome-wide binding profiles from chromatin immunoprecipitation-sequencing (ChIP-seq) studies. The dynamic interplay between ERRα and its newly uncovered cofactor Host cell factor C1 (HCFC1) was further investigated by loss-of-function studies in hepatocytes. Results Characterization of the hepatic ERRα chromatin interactome led to the identification of 48 transcriptional interactors of which 42 were previously unknown including HCFC1. Interrogation of available ChIP-seq binding profiles highlighted oxidative phosphorylation (OXPHOS) under the control of a complex regulatory network between ERRα and multiple cofactors. While ERRα and HCFC1 were found to bind to a large set of common genes, only a small fraction showed their co-localization, found predominately near the transcriptional start sites of genes particularly enriched for components of the mitochondrial respiratory chain. Knockdown studies demonstrated inverse regulatory actions of ERRα and HCFC1 on OXPHOS gene expression ultimately dictating the impact of their loss-of-function on mitochondrial respiration. Conclusions Our work unveils a repertoire of previously unknown transcriptional partners of ERRα comprised of chromatin modifiers and transcription factors thus advancing our knowledge of how ERRα regulates metabolic transcriptional programs.

			Action	DRS
	BSP-175X.csv	Csv
	BSP-350X-SEC.csv	Csv
	BSP-350X.csv	Csv
	BSP-700X.csv	Csv
	DNAPKcs-175X-DGS.raw	Raw