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Phosphorylation-dependent PIH1D1 interactions define substrate specificity of the R2TP cochaperone complex

DOI: 10.1016/j.celrep.2014.03.013 DOI Help
PMID: 24656813 PMID Help

Authors: Zuzana Hořejší (London Research Institute) , Lasse Stach (MRC National Institute for Medical Research) , Thomas G. Flower (MRC National Institute for Medical Research) , Dhira Joshi (London Research Institute) , Helen Flynn (London Research Institute) , J. mark Skehel (London Research Institute) , Nicola J. O’reilly (London Research Institute) , Roksana W. Ogrodowicz (MRC National Institute for Medical Research) , Stephen J. Smerdon (MRC National Institute for Medical Research) , Simon J. Boulton (London Research Institute)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Reports , VOL 7 (1) , PAGES 19 - 26

State: Published (Approved)
Published: April 2014

Open Access Open Access

Abstract: The R2TP cochaperone complex plays a critical role in the assembly of multisubunit machines, including small nucleolar ribonucleoproteins (snoRNPs), RNA polymerase II, and the mTORC1 and SMG1 kinase complexes, but the molecular basis of substrate recognition remains unclear. Here, we describe a phosphopeptide binding domain (PIH-N) in the PIH1D1 subunit of the R2TP complex that preferentially binds to highly acidic phosphorylated proteins. A cocrystal structure of a PIH-N domain/TEL2 phosphopeptide complex reveals a highly specific phosphopeptide recognition mechanism in which Lys57 and 64 in PIH1D1, along with a conserved DpSDD phosphopeptide motif within TEL2, are essential and sufficient for binding. Proteomic analysis of PIH1D1 interactors identified R2TP complex substrates that are recruited by the PIH-N domain in a sequence-specific and phosphorylation-dependent manner suggestive of a common mechanism of substrate recognition. We propose that protein complexes assembled by the R2TP complex are defined by phosphorylation of a specific motif and recognition by the PIH1D1 subunit.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I02-Macromolecular Crystallography

Added On: 23/11/2015 15:25


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)