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

Arjuna Ratnayaka, Luminita Paraoan, Dave G Spiller, Paul Hiscott, Glyn Nelson, Michael R H White, Ian Grierson

Research output: Contribution to journalArticle (journal)peer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1135-9
Number of pages5
JournalExperimental Eye Research
Volume84
Issue number6
DOIs
Publication statusPublished - 1 Jun 2007

Keywords

  • Cystatin C
  • Cystatins/genetics
  • Genetic Predisposition to Disease
  • Golgi Apparatus/metabolism
  • Humans
  • Macular Degeneration/genetics
  • Mitochondria/metabolism

Fingerprint

Dive into the research topics of 'A dual Golgi- and mitochondria-localised Ala25Ser precursor cystatin C: an additional tool for characterising intracellular mis-localisation leading to increased AMD susceptibility'. Together they form a unique fingerprint.

Cite this