Big stride in understanding PP1, the ubiquitous enzyme

In the Proceedings of the National Academy of Sciences, a team of scientists at Brown University reports a major step forward in determining the specific behavior of the ubiquitous enzyme PP1 implicated in a wide range of diseases including cancer.PP1, whose role is to enable the passage of molecular messages among cells, is found pretty much everywhere in the body. Its wide range of responsibilities means it is essential to many healthy functions and, when things go wrong, to diseases. But its very versatility has prevented it from being a target for drug development, said Rebecca Page, associate professor of biology at Brown and the paper’s corresponding author.”The amazing thing about PP1 is that no one has wanted to touch it for the most part as a drug target because PP1 is involved in nearly every biological process,” Page said. “It’s not like you could just target the PP1 active site for, let’s say, diabetes because then you are going to affect drug addiction, Alzheimer’s disease and all these other diseases at the same time.”In other words, make a medicine to block PP1 in one bodily context and you’d ruin it in all other contexts. Structural biologists such as Page and Brown co-author Wolfgang Peti have therefore been eager to learn what makes PP1 behave in specific ways in specific situations.The key is the way PP1 binds with more than 200 different regulatory proteins. Scientists know of these proteins and know the sequences of amino acids that compose them, but they don’t know their structure or how they actually guide PP1.”The ability to predict how these PP1 interacting proteins bind PP1 from sequence alone is still missing,” Page and her colleagues wrote in PNAS.Now, through experiments in which her team including lead author Meng Choy combined NMR spectroscopy, X-ray crystallography and techniques in biochemistry, she has learned how PP1 binds to a targeting protein called PNUTS, forming “binding motifs.” That knowledge, combined with what she learned in earlier studies about two other targeting proteins — NIPP1 and spinophilin — has allowed her team to predict how PP1 binds with 43 of the 200 regulatory proteins that give it specific behavior.”What this work in conjunction with two of our previous structures allowed us to do was to define two entirely new motifs,” she said. “From that, comparing the sequences with the known proteins that interact with PP1 whose structures we don’t have, we were able to predict that 20 percent of them likely interact in a way that is similar to these three proteins.”So by resolving the structure of just three proteins with PP1, Page now has the means to understand the binding of many proteins without having to resolve their structure. Instead she need only know the few motifs and the proteins’ sequences.As for PP1’s interactions with the other 80 percent or so of regulatory proteins, those remain a mystery. But Page said the success her team has had in the lab working with PP1 and resolving key motifs makes her optimistic that those interactions can be solved, too.Story Source:The above story is based on materials provided by Brown University. Note: Materials may be edited for content and length.

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A new role for sodium in the brain

Aug. 20, 2013 — Researchers at McGill University have found that sodium — the main chemical component in table salt — is a unique “on/off” switch for a major neurotransmitter receptor in the brain. This receptor, known as the kainate receptor, is fundamental for normal brain function and is implicated in numerous diseases, such as epilepsy and neuropathic pain.Prof. Derek Bowie and his laboratory in McGill’s Department of Pharmacology and Therapeutics, worked with University of Oxford researchers to make the discovery. By offering a different view of how the brain transmits information, their research highlights a new target for drug development. The findings are published in the journal Nature Structural & Molecular Biology.Balancing kainate receptor activity is the key to maintaining normal brain function. For example, in epilepsy, kainate activity is thought to be excessive. Thus, drugs which would shut down this activity are expected to be beneficial.”It has been assumed for decades that the “on/off” switch for all brain receptors lies where the neurotransmitter binds,” says Prof. Bowie, who also holds a Canada Research Chair in Receptor Pharmacology. “However, we found a completely separate site that binds individual atoms of sodium and controls when kainate receptors get turned on and off.”The sodium switch is unique to kainate receptors, which means that drugs designed to stimulate this switch, should not act elsewhere in the brain. …

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Unusual antibodies in cows suggest new ways to make medicines for people

June 6, 2013 — Humans have been raising cows for their meat, hides and milk for millennia. Now it appears that the cow immune system also has something to offer. A new study led by scientists from The Scripps Research Institute (TSRI) focusing on an extraordinary family of cow antibodies points to new ways to make human medicines.”These antibodies’ structure and their mechanism for creating diversity haven’t been seen before in other animals’ antibodies,” said Vaughn V. Smider, assistant professor of cell and molecular biology at TSRI and principal investigator for the study, which appears as the cover story in the June 6, 2013 issue of the journal Cell.Defense Against InfectionAntibodies, part of our immune system, are large proteins that resemble lobsters — with a tail and two identical arms for grabbing specific targets (called “antigens,” often parts of bacteria or viruses). At the business end of each arm is a small set of protein loops called complementarity-determining regions or CDRs, which actually do the grabbing. By rearranging and mutating the genes that code for CDRs, an animal’s immune system can generate a vast and diverse population of antibodies — which collectively can bind to just about any of the body’s foreign invaders.In humans and in many other mammals, most of an antibody’s specificity for a target is governed by the largest CDR region, CDR H3. Researchers have been finding hints that an unusually long version of this domain can sometimes be the key to a successful defense against a dangerous infection. For example, in a study reported in Nature last August, Ian A. Wilson, who is Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI, and collaborators isolated an anti-HIV antibody with a long CDR H3 region — twice normal length — which allows it to grab a crucial structure on the virus and thereby neutralize the infectivity of most HIV strains.Waithaka Mwangi, assistant professor in the Texas A&M College of Veterinary Medicine and Biomedical Sciences (CVM) and an author on the Cell paper, suggests thinking of these long CDRs as a probe on a thin extended scaffold that can fit narrow crevices to reach and bind unique hidden pathogen determinants that ordinary antibodies cannot.Learning from NatureReports on these antibodies recently caught the interest of Smider, whose area of research includes finding new ways to generate therapeutic antibody proteins. “We started thinking about how we could make these long CDR3s that are so rare in humans, and we knew from the literature that cows make even longer ones all the time,” he said.To investigate, Smider assembled a collaboration that included the TSRI laboratories of Wilson and Peter G. …

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