![]() This exciting paper describes, at atomic resolution, the structural features of a non-native folding intermediate that are critical for amyloidogenic aggregation.Ĭhiti, F. ![]() Conformational conversion during amyloid formation at atomic resolution. Proteome-wide analysis of chaperonin-dependent protein folding in Escherichia coli. Cellular mechanisms of membrane protein folding. This seminal study puts forward the idea that chaperones function in buffering the otherwise deleterious consequences of mutations. Hsp90 as a capacitor for morphological evolution. Chaperonin overexpression promotes genetic variation and enzyme evolution. Protein aggregation in crowded environments. Equilibrium intermediates in the reversible unfolding of firefly ( Photinus pyralis) luciferase. Molecular chaperones in cellular protein folding. Adapting proteostasis for disease intervention. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Biological and chemical approaches to diseases of proteostasis deficiency. Function and structure of inherently disordered proteins. An expanding arsenal of experimental methods yields an explosion of insights into protein folding mechanisms. Protein folding - a perspective from theory and experiment. For further information, please contact the cited source.Dobson, C. Note: material may have been edited for length and content. This article has been republished from the following materials. CHAPERONE PROTEIN ACTIVATORZn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis. Reference: Weiss A, Murdoch CC, Edmonds KA, et al. “This opens up an exciting new area of biology, where we have these regulatory factors controlling a number of different physiological processes through metal insertion.” “We think that when the body is starved for zinc, ZNG1 ensures that zinc gets delivered to the most important zinc-containing proteins,” Skaar said. Mutation of the ZNG1 gene in zebrafish and mouse models caused reduced cellular proliferation and mitochondrial dysfunction - consistent with growth defects observed for zinc deficiency.Ĭollectively, the biochemical, structural, genetic and pharmacological studies using a variety of model systems demonstrated a critical role for ZNG1 in regulating cellular zinc homeostasis. METAP1 removes the initial amino acid on about half of newly synthesized proteins, contributing to protein stability, maturation and cellular location.Ĭo-corresponding senior author David Giedroc, PhD, and his group at Indiana University collaborated on the biochemical studies of ZNG1 and its interaction with and activation of METAP1. Using human, mouse and zebrafish versions of ZNG1 as “bait” to discover ZNG-interacting proteins, they identified the enzyme METAP1 as a client for zinc insertion and fully characterized its interaction with ZNG1. ![]() The researchers found that ZNG1 is conserved from yeast to humans. “We think it may be one of the most important regulatory strategies by which humans cope with severe zinc starvation, which is one of the most important public health issues in the world.” “This is the first identified protein that puts zinc into other proteins,” said Skaar, who is also director of the Vanderbilt Institute for Infection, Immunology, and Inflammation. ![]() Goodpasture Professor of Pathology, Microbiology and Immunology and co-corresponding senior author of the Cell paper.Īndy Weiss, PhD, and Caitlin Murdoch, PhD, postdoctoral fellows in Skaar’s group, are co-first authors of the study describing the zinc metallochaperone, which the researchers - in collaboration with an international gene nomenclature committee - named ZNG1 (for zinc regulated GTPase metalloprotein activator 1). It’s remarkable because so many proteins require metal cofactors,” said Eric Skaar, PhD, MPH, Ernest W. “There’s been a huge gap in the field of metal biology, where we have been unable to identify metallochaperones. The findings, reported in the journal Cell, shed light on the public health issue of zinc deficiency and open an entirely new area of biology for exploration. Now, a team led by Vanderbilt researchers has described and characterized the first zinc metallochaperone: a protein that puts zinc into other “client” proteins. The World Health Organization considers zinc deficiency a leading contributor to disease and death.ĭespite zinc’s critical role, however, it has not been clear how the metal gets put into proteins that use it or how our cells respond to zinc deficiency. We acquire zinc by eating it - in foods or multivitamin supplements - but up to 30% of people in some parts of the world are at risk for zinc deficiency, which can cause slowed growth, impaired immune function, neurological disorders and cancers. We need zinc: one-tenth of the proteins in our cells require this metal for their normal functions in all aspects of cell metabolism. ![]()
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