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

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

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.

Cystatin C, Cystatins, Genetic Predisposition to Disease, Golgi Apparatus, Humans, Macular Degeneration, Mitochondria, Letter, Research Support, Non-U.S. Gov't
0014-4835
1135-9
Ratnayaka, Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Paraoan, Luminita
252bc6c9-e9b1-4bbb-a2d3-d7fb91826b0e
Spiller, Dave G
e2d4ae55-26f1-435f-88b7-cded8d3ebc56
Hiscott, Paul
c5f18179-36ab-4466-98a3-906e6638e10a
Nelson, Glyn
c3556400-ab7e-452e-81c7-a580f86f9821
White, Michael R H
d0d97c08-20c6-4452-a7f4-db92ae05109c
Grierson, Ian
b7edfcbe-f96e-4fe9-a5f1-b235300d011a
Ratnayaka, Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Paraoan, Luminita
252bc6c9-e9b1-4bbb-a2d3-d7fb91826b0e
Spiller, Dave G
e2d4ae55-26f1-435f-88b7-cded8d3ebc56
Hiscott, Paul
c5f18179-36ab-4466-98a3-906e6638e10a
Nelson, Glyn
c3556400-ab7e-452e-81c7-a580f86f9821
White, Michael R H
d0d97c08-20c6-4452-a7f4-db92ae05109c
Grierson, Ian
b7edfcbe-f96e-4fe9-a5f1-b235300d011a

Ratnayaka, Arjuna, Paraoan, Luminita, Spiller, Dave G, Hiscott, Paul, Nelson, Glyn, White, Michael R H and Grierson, Ian (2007) A dual Golgi- and mitochondria-localised Ala25Ser precursor cystatin C: an additional tool for characterising intracellular mis-localisation leading to increased AMD susceptibility. Experimental Eye Research, 84 (6), 1135-9. (doi:10.1016/j.exer.2006.01.030).

Record type: Article

Abstract

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.

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More information

e-pub ahead of print date: 25 April 2006
Published date: June 2007
Keywords: Cystatin C, Cystatins, Genetic Predisposition to Disease, Golgi Apparatus, Humans, Macular Degeneration, Mitochondria, Letter, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 422429
URI: http://eprints.soton.ac.uk/id/eprint/422429
ISSN: 0014-4835
PURE UUID: 4788bd92-4ed2-4096-ba66-03a78038cb36
ORCID for Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

Catalogue record

Date deposited: 24 Jul 2018 16:30
Last modified: 05 Nov 2019 01:37

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Contributors

Author: Luminita Paraoan
Author: Dave G Spiller
Author: Paul Hiscott
Author: Glyn Nelson
Author: Michael R H White
Author: Ian Grierson

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