Role of a non-canonical surface of Rad6 in ubiquitin conjugating activity

ABSTRACT Rad6 is a yeast E2 ubiquitin conjugating enzyme that monoubiquitinates histone H2B in conjunction with the E3, Bre1, but can non-specifically modify histones on its own. We determined the crystal structure of a Rad6∼Ub thioester mimic, which revealed a network of interactions in the crystal in which the ubiquitin in one conjugate contacts Rad6 in another. The region of Rad6 contacted is located on the distal face of Rad6 opposite the active site, but differs from the canonical E2 backside that mediates free ubiquitin binding and polyubiquitination activity in other E2 enzymes. We find that free ubiquitin interacts weakly with both non-canonical and canonical backside residues of Rad6 and that mutations of non-canonical residues have deleterious effects on Rad6 activity comparable to those observed to mutations in the canonical E2 backside. The effect of non-canonical backside mutations is similar in the presence and absence of Bre1, indicating that contacts with non-canonical backside residues govern the intrinsic activity of Rad6. Our findings shed light on the determinants of intrinsic Rad6 activity and reveal new ways in which contacts with an E2 backside can regulate ubiquitin conjugating activity

Shock-wave solutions of the einstein equations: The Oppenheimer-Snyder model of gravitational collapse extended to the case of non-zero pressure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46164/1/205_2004_Article_BF00386247.pd

Speed/Accuracy Trade-Off between the Habitual and the Goal-Directed Processes

Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time

Resolving contradictions between overdetermined NMR cross-correlation rates

A graphical construction was proposed for the complementarity of various cross-correlation rates for the detn. of dihedral angles. Motional fluctuations around the dihedral angles taken into account. The detn. of the conformation of 2 consecutive peptide subunits by the measurement of 4 complementary cross-correlation rates is illustrated. [on SciFinder (R)

Cross-correlated chemical shift modulation: A signature of slow internal motions in proteins

A novel NMR expt. allows one to characterize slow motion in macromols. The method exploits the fact that motions, such as rotation about dihedral angles, induce correlated fluctuations of the isotropic chem. shifts of the nuclei in the vicinity. The relaxation of two-spin coherences involving Ca and Cb nuclei in proteins provides information about correlated fluctuations of the isotropic chem. shifts of Ca and Cb. The difference between the relaxation rates of double- and zero-quantum coherences C+a C+b and C+a C-b is shown to be affected by cross-correlated chem. shift modulation. In ubiquitin, evidence for slow motion is found in loops or near the ends of b-strands and a-helixes. [on SciFinder (R)