Spying on shape-shifting enzyme
The enzyme CaMKII plays a central role in translating fluctuations of cellular calcium levels into signals that mediate many biological processes – from heart rhythms to learning and memory. The enzyme has three main pieces, or domains, which change shape (conformation) to activate the enzyme. A more detailed understanding of this shape-shifting is necessary to design therapies targeting the enzyme.
Using molecular “spies” (spin labels) to visualize these changes, Hassane Mchaourab, Ph.D., Roger Colbran, Ph.D., and colleagues found that the business end (the “kinase” domain) is kept in an inhibited state by the conformational qualities of another domain (the regulatory domain). Binding of calmodulin – a calcium-binding protein that “senses” calcium fluctuations – to the regulatory domain induces structural changes that activate the kinase domain and enhance the enzyme’s interaction with calmodulin.
The findings, published recently in The EMBO Journal, offer a dynamic picture of CaMKII activation which can potentially inform development of new therapeutic strategies for neurological, psychiatric or cardiac diseases. The research was supported by the Vanderbilt University IDEAS program, a trans-institutional program to foster collaborations at Vanderbilt.
— Melissa Marino
Smell test tells disorders apart
Pure autonomic failure (PAF) and multiple system atrophy (MSA) are rare disorders that affect the autonomic nervous system – the control system for sub-conscious functions including blood pressure, digestion and breathing. MSA is more progressive and rapidly fatal, so a simple test that can distinguish the two disorders would be useful.
Emily Garland, Ph.D., and colleagues evaluated odor identification in patients with PAF, MSA or another disorder – dopamine beta-hydroxylase deficiency (DBHD), in which patients have intact autonomic neurons but do not produce the neurotransmitter norepinephrine. The researchers assessed olfactory function using UPSIT, the University of Pennsylvania Smell Identification Test, and found that odor identification was significantly impaired in patients with PAF, but not in patients with MSA or DBHD.
The findings, reported in the Feb. 1 issue of Neurology, suggest that UPSIT may be useful in the differential diagnosis between PAF and MSA. They also shed light on olfactory function by showing that certain neuronal pathways are important, but that norepinephrine is not essential.
— Leigh MacMillan
Sex differences in schizophrenia signals
Schizophrenia, a severe mental disorder that is more common in males, may result from modifications of critical signaling pathways during the development of the brain. The adult onset of schizophrenia-associated behaviors can be studied in rats that have had part of the brain injured after birth (neonatal ventral hippocampal lesion, NVHL).
Eugenia Gurevich, Ph.D., and colleagues examined alterations in signaling pathways in male and female adult rats with NVHL. They report in the February International Journal of Neuropsychopharmacology that the basal activity of ERK and Akt signaling pathways (in control rats) was higher in females than in males, and that NVHL reduced signaling activity in both sexes. Females had lower concentrations of GRK3 and GRK5 – proteins that turn off G-protein coupled receptor signaling – than males, and NVHL caused GRK5 to increase in a brain region in females to match the control male level.
The findings demonstrate sex differences in the expression and activity of signaling molecules that may underlie differential susceptibility of males and females to schizophrenia.
— Leigh MacMillan
Protein combos keep cells straight
The epithelial cells that form our organ linings have distinct sides (e.g., up/down or top/bottom). This polarity is important in nutrient transport and exclusion of harmful agents. Defects in this polarity can break down these critical boundaries and lead to toxicity or diseases like microvillus inclusion disease, a severe form of neonatal diarrheal disease.
James R. Goldenring, M.D., Ph.D., Joseph Roland, Ph.D., and colleagues now show that interactions between the “motor” protein Myosin VB (Myo5B) and multiple Rab proteins are involved in the complex trafficking processes that establish polarity in epithelial cells. The investigators examined the contributions of Rab/Myo5B interactions with specific pathways using Myo5B mutants that lacked the ability to bind to certain Rab proteins.
They found that different combinations of Rab proteins with Myo5B control distinct processes of membrane regulation and trafficking pathways. The findings, reported in the Feb. 15 Proceedings of the National Academy of Sciences, offer insight into disruption of polarized membranes and, potentially, how they might be repaired.
— Melissa Marino/Mimi Eckhard
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