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Restoration of Proper Trafficking to the Cell Surface for Membrane Proteins Harboring Cysteine Mutations Angelica Lopez-Rodriguez, Miguel Holmgren* Neurophysiology Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, United States of America Abstract A common phenotype for many genetic diseases is that the cell is unable to deliver full-length membrane proteins to the cell surface. For some forms of autism, hereditary spherocytosis and color blindness, the culprits are single point mutations to cysteine. We have studied two inheritable cysteine mutants of cyclic nucleotide-gated channels that produce achromatopsia, a common form of severe color blindness. By taking advantage of the reactivity of cysteine’s sulfhydryl group, we modified these mutants with chemical reagents that attach moieties with similar chemistries to the wild-type amino acids’ side chains. We show that these modifications restored proper delivery to the cell membrane. Once there, the channels exhibited normal functional properties. This strategy might provide a unique opportunity to assess the chemical nature of membrane protein traffic problems. Citation: Lopez-Rodriguez A, Holmgren M (2012) Restoration of Proper Trafficking to the Cell Surface for Membrane Proteins Harboring Cysteine Mutations. PLoS ONE 7(10): e47693. doi:10.1371/journal.pone.0047693 Editor: Ruben Claudio Aguilar, Purdue University, United States of America Received July 5, 2012; Accepted September 17, 2012; Published October 17, 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Co