Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If You Use a Screen Reader

This content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.

Endoplasmic Reticulum Retention Is a Common Defect Associated with Tyrosinase-Negative Albinism

Ruth Halaban, Sherri Svedine, Elaine Cheng, Yoel Smicun, Rebecca Aron and Daniel N. Hebert
Proceedings of the National Academy of Sciences of the United States of America
Vol. 97, No. 11 (May 23, 2000), pp. 5889-5894
Stable URL: http://www.jstor.org/stable/122552
Page Count: 6
  • Read Online (Free)
  • Subscribe ($19.50)
  • Cite this Item
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Endoplasmic Reticulum Retention Is a Common Defect Associated with Tyrosinase-Negative Albinism
Preview not available

Abstract

Tyrosinase is a melanocyte-specific enzyme critical for the synthesis of melanin, a process normally restricted to a post-Golgi compartment termed the melanosome. Loss-of-function mutations in tyrosinase are the cause of oculocutaneous albinism, demonstrating the importance of the enzyme in pigmentation. In the present study, we explored the possibility that trafficking of albino tyrosinase from the endoplasmic reticulum (ER) to the Golgi apparatus and beyond is disrupted. Toward this end, we analyzed the common albino mouse mutation Tyr(C85S), the frequent human albino substitution TYR(T373K), and the temperature-sensitive tyrosinase TYR(R402Q)/Tyr(H402A) found in humans and mice, respectively. Intracellular localization was monitored in albino melanocytes carrying the native mutation, as well as in melanocytes ectopically expressing green fluorescent protein-tagged tyrosinase. Enzymatic characterization of complex glycans and immunofluorescence colocalization with organelle-specific resident proteins established that all four mutations produced defective proteins that were retained in the ER. TYR(R402Q)/Tyr(H402A) Golgi processing and transport to melanosomes were promoted at the permissive temperature of 32 degrees C, but not at the nonpermissive 37 degrees C temperature. Furthermore, evidence of protein misfolding was demonstrated by the prolonged association of tyrosinase mutants with calnexin and calreticulin, known ER chaperones that play a key role in the quality-control processes of the secretory pathway. From these results we concluded that albinism, at least in part, is an ER retention disease.

Page Thumbnails

  • Thumbnail: Page 
5889
    5889
  • Thumbnail: Page 
5890
    5890
  • Thumbnail: Page 
5891
    5891
  • Thumbnail: Page 
5892
    5892
  • Thumbnail: Page 
5893
    5893
  • Thumbnail: Page 
5894
    5894