A mutation within the transmembrane domain of melanosomal protein Silver (Pmel17) changes lumenal fragment interactions

Regina Kuliawat, Laura Santambrogio

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Melanocytes synthesize and store melanin within tissue-specific organelles, the melanosomes. Melanin deposition takes place along fibrils found within these organelles and fibril formation is known to depend on trafficking of the membrane glycoprotein Silver/Pmel17. However, correctly targeted, full-length Silver/Pmel17 cannot form fibers. Proteolytic processing in endosomal compartments and the generation of a lumenal Mα fragment that is incorporated into amyloid-like structures is also essential. Dominant White (DWhite), a mutant form of Silver/Pmel17 first described in chicken, causes disorganized fibers and severe hypopigmentation due to melanocyte death. Surprisingly, the DWhite mutation is an insertion of three amino acids into the transmembrane domain; the DWhite-Mα fragment is unaffected. To determine the functional importance of the transmembrane domain in organized fibril assembly, we investigated membrane trafficking and multimerization of Silver/Pmel17/DWhite proteins. We demonstrate that the DWhite mutation changes lipid interactions and disulfide bond-mediated associations of lumenal domains. Thus, partitioning into membrane microdomains and effects on conformation explain how the transmembrane region may contribute to the structural integrity of Silver/Pmel17 oligomers or influence toxic, amyloidogenic properties.

Original languageEnglish (US)
Pages (from-to)653-667
Number of pages15
JournalEuropean Journal of Cell Biology
Volume88
Issue number11
DOIs
StatePublished - Nov 1 2009

Keywords

  • Amyloid fibrils
  • Dominant White
  • Melanosome biogenesis
  • Protein sorting
  • Silver/Pmel17

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

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