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Updated: Jun 21, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
A mutation within the transmembrane domain of melanosomal protein Silver (Pmel17) changes lumenal fragment
Regina Kuliawat1, Laura Santambrogio
1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. kuliawat@aecom.yu.edu
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 Malpha 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-Malpha 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.
Insights
The Silver/Pmel17 transmembrane domain is crucial for melanin-storing melanosome fibril assembly. A mutation disrupts lipid interactions and protein conformation, leading to disorganized fibers and hypopigmentation.
Area of Science:
- Cell Biology
- Biochemistry
- Genetics
Background:
- Melanosomes are organelles where melanocytes synthesize and store melanin.
- Melanin deposition relies on fibril formation within melanosomes, dependent on Silver/Pmel17 trafficking.
- Full-length Silver/Pmel17 requires proteolytic processing and Malpha fragment generation for fiber formation.
Purpose of the Study:
- To investigate the functional importance of the Silver/Pmel17 transmembrane domain in melanosome fibril assembly.
- To understand how the Dominant White (DWhite) mutation affects protein trafficking and multimerization.
- To elucidate the role of the transmembrane region in structural integrity and potential toxic properties of Silver/Pmel17.
Main Methods:
- Investigated membrane trafficking of Silver/Pmel17/DWhite proteins.
- Analyzed protein multimerization.
- Examined lipid interactions and disulfide bond-mediated associations.
Main Results:
- The DWhite mutation, an insertion in the transmembrane domain, leads to disorganized fibers and hypopigmentation.
- The DWhite mutation alters lipid interactions and disulfide bond associations of lumenal domains.
- Transmembrane domain alterations affect Silver/Pmel17 partitioning into membrane microdomains and protein conformation.
Conclusions:
- The transmembrane domain plays a critical role in the structural integrity of Silver/Pmel17 oligomers.
- Alterations in the transmembrane domain can influence the amyloidogenic properties of Silver/Pmel17.
- Understanding these mechanisms provides insight into melanosome biogenesis and pigmentary disorders.
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