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Identification of critical amino acid residues in the regulatory N-terminal domain of PMEL
- Source :
- Scientific Reports, Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group UK, 2021.
-
Abstract
- The pigment cell-specific protein PMEL forms a functional amyloid matrix in melanosomes onto which the pigment melanin is deposited. The amyloid core consists of a short proteolytic fragment, which we have termed the core-amyloid fragment (CAF) and perhaps additional parts of the protein, such as the PKD domain. A highly O-glycosylated repeat (RPT) domain also derived from PMEL proteolysis associates with the amyloid and is necessary to establish the sheet-like morphology of the assemblies. Excluded from the aggregate is the regulatory N-terminus, which nevertheless must be linked in cis to the CAF in order to drive amyloid formation. The domain is then likely cleaved away immediately before, during, or immediately after the incorporation of a new CAF subunit into the nascent amyloid. We had previously identified a 21 amino acid long region, which mediates the regulatory activity of the N-terminus towards the CAF. However, many mutations in the respective segment caused misfolding and/or blocked PMEL export from the endoplasmic reticulum, leaving their phenotype hard to interpret. Here, we employ a saturating mutagenesis approach targeting the motif at single amino acid resolution. Our results confirm the critical nature of the PMEL N-terminal region and identify several residues essential for PMEL amyloidogenesis.
- Subjects :
- Protein Folding
Amyloid
Protein subunit
Proteolysis
Science
Endoplasmic Reticulum
Article
Protein Domains
medicine
Humans
Amino Acid Sequence
Amino Acids
Melanosome
chemistry.chemical_classification
Multidisciplinary
Multivesicular bodies
Melanosomes
medicine.diagnostic_test
Endoplasmic reticulum
Mutagenesis
Amino acid
PMEL
Cell biology
Protein Transport
chemistry
Mutation
Medicine
Protein aggregation
Lysosomes
Subcellular Fractions
gp100 Melanoma Antigen
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....5b7f2448038718ed4cfd4ee038b479cf