A dual Golgi- and mitochondria-localised Ala25Ser precursor cystatin C: An additional tool for characterising intracellular mis-localisation leading to increased AMD susceptibility

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  2. Dr Glyn Nelson
Author(s)Ratnayaka A, Paraoan L, Spiller DG, Hiscott P, Nelson G, White MRH, Grierson I
Publication type Letter
JournalExperimental Eye Research
Year2007
Volume84
Issue6
Pages1135-1139
ISSN (print)0014-4835
ISSN (electronic)1096-0007
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An artificial mutant Ala25Ser precursor cystatin C was created to help elucidate the cause of intracellular mis-localisation of the biochemically related variant B (Ala25Thr) precursor cystatin C to the mitochondria. Homozygotes of variant B precursor cystatin C were reported to carry an increased susceptibility to developing the exudative form of AMD. Ala25Ser precursor cystatin C shows a dual distribution to the Golgi apparatus and to the mitochondria. This localisation is thus intermediary between that of wild-type cystatin C (targeted to ER/Golgi compartment) and that of variant B precursor cystatin C. Furthermore, the level of secretion of Ala25Ser cystatin C by RPE cells is intermediary between wild type and variant B cystatin C. Ala25Ser precursor cystatin C thus represents a biochemical intermediate between the wild type and the AMD-associated cystatin C and as such, is a novel tool for the investigation of the mechanism of intracellular mis-localisation of variant B cystatin C. Our findings further support the hypothesis that substitution of the alanine residue in the penultimate position of precursor cystatin C signal sequence with a less hydrophobic amino acid residue, such as threonine (as in variant B cystatin C) or serine is sufficient to impair the intracellular trafficking and processing of the protein. (c) 2006 Elsevier Ltd. All rights reserved.
URLhttp://dx.doi.org/10.1016/j.exer.2006.01.030
DOI10.1016/j.exer.2006.01.030
Notes179HC Times Cited:0 Cited References Count:16
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