Long-Range Intra-Protein Communication Can Be Transmitted by Correlated Side-Chain Fluctuations Alone

Allosteric regulation is a key component of cellular communication, but the way in which information is passed from one site to another within a folded protein is not often clear. While backbone motions have long been considered essential for long-range information conveyance, side-chain motions have rarely been considered. In this work, we demonstrate their potential utility using Monte Carlo sampling of side-chain torsional angles on a fixed backbone to quantify correlations amongst side-chain inter-rotameric motions. Results indicate that long-range correlations of side-chain fluctuations can arise independently from several different types of interactions: steric repulsions, implicit solvent interactions, or hydrogen bonding and salt-bridge interactions. These robust correlations persist across the entire protein (up to 60 Å in the case of calmodulin) and can propagate long-range changes in side-chain variability in response to single residue perturbations

A Linear Framework for Time-Scale Separation in Nonlinear Biochemical Systems

Cellular physiology is implemented by formidably complex biochemical systems with highly nonlinear dynamics, presenting a challenge for both experiment and theory. Time-scale separation has been one of the few theoretical methods for distilling general principles from such complexity. It has provided essential insights in areas such as enzyme kinetics, allosteric enzymes, G-protein coupled receptors, ion channels, gene regulation and post-translational modification. In each case, internal molecular complexity has been eliminated, leading to rational algebraic expressions among the remaining components. This has yielded familiar formulas such as those of Michaelis-Menten in enzyme kinetics, Monod-Wyman-Changeux in allostery and Ackers-Johnson-Shea in gene regulation. Here we show that these calculations are all instances of a single graph-theoretic framework. Despite the biochemical nonlinearity to which it is applied, this framework is entirely linear, yet requires no approximation. We show that elimination of internal complexity is feasible when the relevant graph is strongly connected. The framework provides a new methodology with the potential to subdue combinatorial explosion at the molecular level

The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27

Understanding the essential functions of the anaphase-promoting complex/cyclosome (APC/C), a multiprotein ubiquitin ligase with key roles in mitosis, ultimately requires high-resolution structural information. This study reports the crystallization of the largest APC/C subcomplex so far, including a full-length dimerized tetratricopeptide repeat (TPR) subunit

Crystal-structure Of Yersinia Protein-tyrosine-phosphatase At 2.5-angstrom And The Complex With Tungstate

PROTEIN tyrosine phosphatases (PTPases) and kinases coregulate the critical levels of phosphorylation necessary for intracellular signalling, cell growth and differentiation(1,2). Yersinia, the causative bacteria of the bubonic plague and other enteric diseases, secrete an active PTPase(3), Yop51, that enters and suppresses host immune cells(4,5). Though the catalytic domain is only similar to 20% identical to human PTP1B(6), the Yersinia PTPase contains all of the invariant residues present in eukaryotic PTPases(7), including the nucleophilic Cys 403 which forms a phosphocysteine intermediate during catalysis(3,8-10). We present here structures of the unliganded (2.5 Angstrom resolution) and tungstate-bound (2.6 Angstrom) crystal forms which reveal that Cys 403 is positioned at the centre of a distinctive phosphate-binding loop. This loop is at the hub of several hydrogen-bond arrays that not only stabilize a bound oxyanion, but may activate Cys 403 as a reactive thiolate. Binding of tungstate triggers a conformational change that traps the oxyanion and swings Asp 356, an important catalytic residue(7), by similar to 6 Angstrom into the active site. The same anion-binding loop in PTPases is also found in the enzyme rhodanese(11).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62819/1/370571a0.pd