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Published on: September 28, 2019
Melanosomal formation of PMEL core amyloid is driven by aromatic residues
Jia Shee Hee1, Susan M Mitchell1, Xinran Liu2
1Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven CT 06519, USA.
Abstract:
PMEL is a pigment cell protein that forms physiological amyloid in melanosomes. Many amyloids and/or their oligomeric precursors are toxic, causing or contributing to severe, incurable diseases including Alzheimer's and prion diseases. Striking similarities in intracellular formation pathways between PMEL and various pathological amyloids including Aβ and PrPSc suggest PMEL is an excellent model system to study endocytic amyloid. Learning how PMEL fibrils assemble without apparent toxicity may help developing novel therapies for amyloid diseases. Here we identify the critical PMEL domain that forms the melanosomal amyloid core (CAF). An unbiased alanine-scanning screen covering the entire region combined with quantitative electron microscopy analysis of the full set of mutants uncovers numerous essential residues. Many of these rely on aromaticity for function suggesting a role for π-stacking in melanosomal amyloid assembly. Various mutants are defective in amyloid nucleation. This extensive data set informs the first structural model of the CAF and provides insights into how the melanosomal amyloid core forms.
Insights
Pigment cell protein (PMEL) forms amyloid fibrils in melanosomes. Identifying key residues and structural models of PMEL amyloid assembly offers insights into treating toxic amyloid diseases like Alzheimer's.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Pigment cell protein (PMEL) forms physiological amyloid structures within melanosomes.
- Pathological amyloids, such as those in Alzheimer's and prion diseases, share similarities with PMEL formation pathways.
- Studying non-toxic PMEL amyloid assembly may reveal therapeutic strategies for amyloid-related diseases.
Purpose of the Study:
- To identify the critical domain of PMEL responsible for forming the melanosomal amyloid core (CAF).
- To elucidate the molecular mechanisms and structural features governing PMEL amyloid assembly.
- To provide a foundation for understanding and potentially treating pathological amyloidosis.
Main Methods:
- An unbiased alanine-scanning mutagenesis screen was performed across the entire PMEL region.
- Quantitative electron microscopy was used to analyze the structural impact of various PMEL mutants.
- A structural model of the CAF was developed based on the experimental data.
Main Results:
- Numerous essential residues within the CAF were identified through the mutagenesis screen.
- Aromatic residues and potential π-stacking interactions were found to be crucial for amyloid assembly.
- Several mutants exhibited defects in amyloid nucleation, providing insights into the initial stages of fibril formation.
- The first structural model of the CAF was generated, detailing its assembly process.
Conclusions:
- The study precisely mapped the critical PMEL domain essential for melanosomal amyloid core formation.
- Key residues and structural interactions, including π-stacking, are vital for PMEL amyloid assembly.
- This research provides a foundational understanding of physiological amyloid formation and its implications for human diseases.
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