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PMEL: a pigment cell-specific model for functional amyloid formation
Brenda Watt1, Guillaume van Niel, Graça Raposo
1Department of Pathology and Laboratory Medicine, Department of Physiology, and Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Abstract:
PMEL is a pigment cell-specific protein responsible for the formation of fibrillar sheets within the pigment organelle, the melanosome. The fibrillar sheets serve as a template upon which melanins polymerize as they are synthesized. The PMEL fibrils are required for optimal pigment cell function, as animals that either lack PMEL expression or express mutant PMEL variants show varying degrees of hypopigmentation and pigment cell inviability. The PMEL fibrils have biophysical properties of amyloid, a protein fold that is frequently associated with neurodegenerative and other diseases. However, PMEL is one of a growing number of non-pathogenic amyloid proteins that contribute to the function of the cell and/or organism that produces them. Understanding how PMEL generates amyloid in a non-pathogenic manner might provide insights into how to avoid toxicity due to pathological amyloid formation. In this review, we summarize and reconcile data concerning the fate of PMEL from its site of synthesis in the endoplasmic reticulum to newly formed melanosomes and the role of distinct PMEL subdomains in trafficking and amyloid fibril formation. We then discuss how its progression through the secretory pathway into the endosomal system might allow for the regulated and non-toxic conversion of PMEL into an ordered amyloid polymer.
Insights
The pigment-dispersing factor (PMEL) protein forms amyloid fibrils essential for melanin production in pigment cells. Understanding this non-pathogenic amyloid formation may prevent toxic amyloid aggregation in diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- The protein PMEL is crucial for forming fibrillar sheets in melanosomes, acting as a template for melanin polymerization.
- PMEL fibrils are essential for pigment cell function; deficiencies lead to hypopigmentation and cell death.
- PMEL fibrils exhibit amyloid properties, a fold often linked to neurodegenerative diseases, but PMEL represents a non-pathogenic amyloid.
Purpose of the Study:
- To review and synthesize data on PMEL's journey from synthesis to melanosome formation.
- To elucidate the role of specific PMEL subdomains in protein trafficking and amyloid fibril assembly.
- To explore how PMEL's pathway through the secretory and endosomal systems facilitates non-toxic amyloid formation.
Main Methods:
- Literature review and data synthesis.
- Analysis of PMEL's biophysical properties and protein folding.
- Examination of PMEL trafficking through the endoplasmic reticulum, secretory pathway, and endosomal system.
Main Results:
- PMEL undergoes a complex trafficking process from synthesis in the ER to melanosomes.
- Distinct PMEL subdomains are critical for its proper trafficking and the formation of amyloid fibrils.
- The progression through the secretory and endosomal pathways appears to regulate PMEL's conversion into ordered, non-pathogenic amyloid.
Conclusions:
- PMEL's amyloid formation is a regulated, non-pathogenic process vital for pigment production.
- Studying PMEL's mechanism offers potential strategies to mitigate toxicity from pathological amyloids.
- Further research into PMEL's structure-function relationship can illuminate therapeutic targets for amyloid-related diseases.
