Functional Amyloid Formation within Mammalian Tissue

By Douglas M. Fowler, Atanas V. Koulov, Christelle Alory-Jost, M. Marks, William E. Balch, J. Kelly. PLoS Biology, 2005

807 citations recorded by the source corpus.

Amyloid is a generally insoluble, fibrous cross-β sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin—a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

Subfields: Cell Biology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/855ddf5c01fb25126281052bcd55334e1c41d244

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. P. Saftig
2. G. Raposo
3. Guillaume van Niel

In Molecular Biology

1. G. Raposo
2. Guillaume van Niel
3. Sabrina Simoes
4. J. Kelly
5. Douglas M. Fowler
6. P. Saftig
7. William E. Balch
8. C. Théry

In Physiology

1. J. Kelly
2. P. Saftig
3. G. Raposo
4. Guillaume van Niel
5. Tuomas P. J. Knowles

Citations in the corpus

• Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. (2017, neutral): “3D structure of Alzheimer’s amyloid-β(1-42) fibrils.”
• Functional amyloid--from bacteria to humans. (2007, background): “The oxidative damage and consequent melanocyte death observed in si/si mice and I/* chickens can be explained by a lack of Ma amyloid, which seems to function to sequester reactive melanogenic precursor compounds such as DHQ within the melanosome [ 12 ].”
• The tetraspanin CD63 regulates ESCRT-independent and dependent endosomal sorting during melanogenesis (2011, background): “Sorting to ILVs correlates with proteolytic processing steps that release the fibrillogenic luminal domain from the transmembrane form of PMEL to initiate amyloid formation (Berson et al., 2001; Berson et al., 2003; Fowler et al., 2006; Kummer et al., 2009).”