Functional Domains and Evolutionary History of the PMEL and GPNMB Family Proteins
| Autor: | Michael A. Walter, W. Ted Allison, Justin A. Jensen, Paul W. Chrystal, Elizabeth Hodges, Tim Footz |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Amyloid
Pharmaceutical Science Sequence Homology Organic chemistry Amyloidogenic Proteins Biology Article Analytical Chemistry 03 medical and health sciences 0302 clinical medicine QD241-441 Tandem repeat Protein Domains Drug Discovery medicine PMEL-17-related family PTHR11861 Gene family Animals Humans pigmentation Amino Acid Sequence Physical and Theoretical Chemistry Gene PKAT family proteins Phylogeny 030304 developmental biology 0303 health sciences GPNMB Membrane Glycoproteins Neurodegeneration neurodegeneration Computational Biology melanosomes Neurodegenerative Diseases functional amyloid medicine.disease Phenotype PMEL Chemistry (miscellaneous) Evolutionary biology Mutation Molecular Medicine Melanocytes 030217 neurology & neurosurgery gp100 Melanoma Antigen |
| Zdroj: | Molecules, Vol 26, Iss 3529, p 3529 (2021) Molecules Volume 26 Issue 12 |
| ISSN: | 1420-3049 |
| Popis: | The ancient paralogs premelanosome protein (PMEL) and glycoprotein nonmetastatic melanoma protein B (GPNMB) have independently emerged as intriguing disease loci in recent years. Both proteins possess common functional domains and variants that cause a shared spectrum of overlapping phenotypes and disease associations: melanin-based pigmentation, cancer, neurodegenerative disease and glaucoma. Surprisingly, these proteins have yet to be shown to physically or genetically interact within the same cellular pathway. This juxtaposition inspired us to compare and contrast this family across a breadth of species to better understand the divergent evolutionary trajectories of two related, but distinct, genes. In this study, we investigated the evolutionary history of PMEL and GPNMB in clade-representative species and identified TMEM130 as the most ancient paralog of the family. By curating the functional domains in each paralog, we identified many commonalities dating back to the emergence of the gene family in basal metazoans. PMEL and GPNMB have gained functional domains since their divergence from TMEM130, including the core amyloid fragment (CAF) that is critical for the amyloid potential of PMEL. Additionally, the PMEL gene has acquired the enigmatic repeat domain (RPT), composed of a variable number of imperfect tandem repeats this domain acts in an accessory role to control amyloid formation. Our analyses revealed the vast variability in sequence, length and repeat number in homologous RPT domains between craniates, even within the same taxonomic class. We hope that these analyses inspire further investigation into a gene family that is remarkable from the evolutionary, pathological and cell biology perspectives. |
| Databáze: | OpenAIRE |
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