NDLI: Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances $Mn^{2+}$ efflux and protects against toxicity

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Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances $Mn^{2+}$ efflux and protects against toxicity

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Linstedt, Adam D. Mukhopadhyay, Somshuvra
Description	Author Affiliation: Mukhopadhyay S ( Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.);
Abstract	P-type ATPases transport a wide array of ions, regulate diverse cellular processes, and are implicated in a number of human diseases. However, mechanisms that increase ion transport by these ubiquitous proteins are not known. SPCA1 is a P-type pump that transports Mn(2+) from the cytosol into the Golgi. We developed an intra-Golgi Mn(2+) sensor and used it to screen for mutations introduced in SPCA1, on the basis of its predicted structure, which could increase its Mn(2+) pumping activity. Remarkably, a point mutation (Q747A) predicted to increase the size of its ion permeation cavity enhanced the sensor response and a compensatory mutation restoring the cavity to its original size abolished this effect. In vivo and in vitro Mn(2+) transport assays confirmed the hyperactivity of SPCA1-Q747A. Furthermore, increasing Golgi Mn(2+) transport by expression of SPCA1-Q747A increased cell viability upon Mn(2+) exposure, supporting the therapeutic potential of increased Mn(2+) uptake by the Golgi in the management of Mn(2+)-induced neurotoxicity.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	2
Volume Number	108
Language	English
Publisher	National Academy of Sciences
Publisher Date	2011-01-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Adenosine Triphosphatases Chemistry Calcium-Transporting ATPases Genetics Physiology Golgi Apparatus Metabolism Manganese Mutation Proton-Translocating ATPases Alanine Cytosol HeLa Cells Models, Molecular Molecular Conformation Phosphorylation Point Mutation Vesicular Transport Proteins Research Support, N.I.H., Extramural Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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