2qnj

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spinqualitylabelsall models 2qnj, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Kinase and Ubiquitin-associated domains of MARK3/Par-1

Overview

The Par-1/MARK protein kinases play a pivotal role in establishing, cellular polarity. This family of kinases contains a unique domain, architecture, in which a ubiquitin-associated (UBA) domain is located, C-terminal to the kinase domain. We have used a combination of x-ray, crystallography and NMR dynamics experiments to understand the interaction, of the human (h) MARK3 UBA domain with the adjacent kinase domain as, compared with ubiquitin. The x-ray crystal structure of the linked hMARK3, kinase and UBA domains establishes that the UBA domain forms a stable, intramolecular interaction with the N-terminal lobe of the kinase domain., However, solution-state NMR studies of the isolated UBA domain indicate, that it is highly dynamic, undergoing conformational transitions that can, be explained by a folding-unfolding equilibrium. NMR titration experiments, indicated that the hMARK3 UBA domain has a detectable but extremely weak, affinity for mono ubiquitin, which suggests that conformational, instability of the isolated hMARK3 UBA domain attenuates binding to, ubiquitin despite the presence of residues typically involved in ubiquitin, recognition. Our data identify a molecular mechanism through which the, hMARK3 UBA domain has evolved to bind the kinase domain, in a fashion that, stabilizes an open conformation of the N- and C-terminal lobes, at the, expense of its capacity to engage ubiquitin. These results may be relevant, more generally to the 30% of UBA domains that lack significant, ubiquitin-binding activity, and they suggest a unique mechanism by which, interaction domains may evolve new binding properties.

About this Structure

2QNJ is a Single protein structure of sequence from Homo sapiens. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.

Reference

Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain., Murphy JM, Korzhnev DM, Ceccarelli DF, Briant DJ, Zarrine-Afsar A, Sicheri F, Kay LE, Pawson T, Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14336-41. Epub 2007 Aug 28. PMID:17726107

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