Computational Tools Identify Novel Mechanisms for Feline Color-Pointed Phenotypes Based on Tyrosinase Mutations
Helen Fenske1, Ingrid R. Niesman2,*
1 Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, USA
2 Department of Biology, San Diego State University, San Diego, CA 92182, USA
* Corresponding Author: Ingrid R. Niesman. Email: 
BIOCELL https://doi.org/10.32604/biocell.2025.071078
Received 31 July 2025; Accepted 30 October 2025; Published online 28 November 2025
Abstract
Objective: Tyrosinase is the rate-limiting enzyme in the generation of melanin. The feline tyrosinase mutation, G302R, confers temperature-sensitive loss of function, resulting in the familiar Siamese cat phenotype. Crystal or cryoEM structures are elusive for any mammalian tyrosinase to date. Protein misfolding is suggested as a basis for phenotypes resulting from mutant tyrosinases, but this hypothesis needs structural confirmation. Our objective for this study is to confirm misfolding of mutant tyrosinase as a basis for temperature-sensitive phenotypes compared to catalytic dysfunction that may be responsible for other tyrosinase mutant breed phenotypes.
Methods: We have employed AlphaFold3 to compare structural alignments of four well-characterized feline tyrosinase mutations to wild type (WT) feline tyrosinase; Siamese G302R, Burmese G227W, Mocha delI274-L312+2aa, and Albino del401-529 lacking the transmembrane and C-terminus domains.
Results: The manifestations of the bulkier side chains of the Siamese positively charged arginine (R) and the Burmese hydrophobic tryptophan (W) are evident locally. But interestingly, the major differences between the structures lie in the usually ignored signal peptide (SP) regions of each mutant. As the maturation of the nascent tyrosinase peptide is highly dependent on accurate and early cleavage of the SP, we hypothesize these structural anomalies may form the basis for misfolded or truncated final enzyme forms, leading to the observed phenotypes seen in these cats.
Conclusions: We have identified enzyme dysfunction and protein misfolding as separate mechanisms for feline coat phenotypes resulting from tyrosinase mutations.
Keywords
Tyrosinase; signal peptide; translation; feline; endoplasmic reticulum (ER) stress; melanin
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