Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response

While numerous small ubiquitin‐like modifier (SUMO) conjugated substrates have been identified, very little is known about the cellular signalling mechanisms that differentially regulate substrate sumoylation. Here, we show that acetylation of SUMO E2 conjugase Ubc9 selectively downregulates the sumoylation of substrates with negatively charged amino acid‐dependent sumoylation motif (NDSM) consisting of clustered acidic residues located downstream from the core ψ‐K‐X‐E/D consensus motif, such as CBP and Elk‐1, but not substrates with core ψ‐K‐X‐E/D motif alone or SUMO‐interacting motif. Ubc9 is acetylated at residue K65 and K65 acetylation attenuates Ubc9 binding to NDSM substrates, causing a reduction in NDSM substrate sumoylation. Furthermore, Ubc9 K65 acetylation can be downregulated by hypoxia via SIRT1, and is correlated with hypoxia‐elicited modulation of sumoylation and target gene expression of CBP and Elk‐1 and cell survival. Our data suggest that Ubc9 acetylation/deacetylation serves as a dynamic switch for NDSM substrate sumoylation and we report a previously undescribed SIRT1/Ubc9 regulatory axis in the modulation of protein sumoylation and the hypoxia response.     

Cellulose-bound Peptide Arrays: Preparation and Applications

Spatial organization of metabolic enzymes may represent a general cellular mechanism to regulate metabolic flux. One recent example of this type of cellular phenomenon is the purinosome, a newly discovered multi-enzyme metabolic assembly that includes all of the enzymes within the de novo purine biosynthetic pathway. Our understanding of the components and regulation of purinosomes has significantly grown in recent years. This paper reviews the purine de novo biosynthesis pathway and its regulation, and presents the evidence supporting the purinosome assembly and disassembly processes under the control of G-protein-coupled receptor (GPCR) signaling. This paper also discusses the implications of purinosome and GPCR regulation in drug discovery.     

GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.     

Age decline in the activity of the Ca2+-sensitive K+ channel of human red blood cells

The Ca(2+)-sensitive K(+) channel of human red blood cells (RBCs) (Gardos channel, hIK1, hSK4) was implicated in the progressive densification of RBCs during normal senescence and in the mechanism of sickle cell dehydration. Saturating RBC Ca(2+) loads were shown before to induce rapid and homogeneous dehydration, suggesting that Gardos channel capacity was uniform among the RBCs, regardless of age. Using glycated hemoglobin as a reliable RBC age marker, we investigated the age-activity relation of Gardos channels by measuring the mean age of RBC subpopulations exceeding a set high density boundary during dehydration. When K(+) permeabilization was induced with valinomycin, the oldest and densest cells, which started nearest to the set density boundary, crossed it first, reflecting conservation of the normal age-density distribution pattern during dehydration. However, when Ca(2+) loads were used to induce maximal K(+) fluxes via Gardos channels in all RBCs (F(max)), the youngest RBCs passed the boundary first, ahead of the older RBCs, indicating that Gardos channel F(max) was highest in those young RBCs, and that the previously observed appearance of uniform dehydration concealed a substantial degree of age scrambling during the dehydration process. Further analysis of the Gardos channel age-activity relation revealed a monotonic decline in F(max) with cell age, with a broad quasi-Gaussian F(max) distribution among the RBCs.     

Multiplicity of control in the basal ganglia: computational roles of striatal subregions

The basal ganglia, in particular the striatum, are central to theories of behavioral control, and often identified as a seat of action selection. Reinforcement learning (RL) models--which have driven much recent experimental work on this region--cast striatum as a dynamic controller, integrating sensory and motivational information to construct efficient and enriching behavioral policies. Befitting this informationally central role, the BG sit at the nexus of multiple anatomical 'loops' of synaptic projections, connecting a wide range of cortical and subcortical structures. Numerous pioneering anatomical studies conducted over the past several decades have meticulously catalogued these loops, and labeled them according to the inferred functions of the connected regions. The specific cotermina of the projections are highly localized to several different subregions of the striatum, leading to the suggestion that these subregions perform complementary but distinct functions. However, until recently, the dominant computational framework outlined only a bipartite, dorsal/ventral, division of striatum. We review recent computational and experimental advances that argue for a more finely fractionated delineation. In particular, experimental data provide extensive insight into unique functions subserved by the dorsomedial striatum (DMS). These functions appear to correspond well with theories of a 'model-based' RL subunit, and may also shed light on the suborganization of ventral striatum. Finally, we discuss the limitations of these ideas and how they point the way toward future refinements of neurocomputational theories of striatal function, bringing them into contact with other areas of computational theory and other regions of the brain.     

FHA: a signal transduction domain with diverse specificity and function

The structure of the FHA domain of the Chfr mitotic checkpoint protein described in this issue of Structure represents one of only a few known structures of this newly discovered phosphoprotein binding domain with diverse function and specificity.