Functional Domains and Evolutionary History of the PMEL and GPNMB Family Proteins

Abstract

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.

Disrupting the Repeat Domain of Premelanosome Protein (PMEL) Produces Dysamyloidosis and Dystrophic Ocular Pigment Reflective of Pigmentary Glaucoma

“…In a recent review, we collated PMEL mutations from patients, from preclinical animal models and from diverse domesticated animal species. This demonstrated a consistent pattern where nonsense and null mutations exhibit recessive inheritance (of pigment and/or ocular defects), whereas missense PMEL mutations exhibit dominant inheritance [17]. The dominant missense mutations in PMEL, including in pigmentary glaucoma patients, suggest the hypothesis that mutant PMEL amyloid in heterozygous animals has intermolecular interactions that disrupt the function of the normal PMEL protein.…”

Identification of gravity‐responsive serum proteins in spaceflight mice using a quantitative proteomic approach with data‐independent acquisition mass spectrometry

“…Mechanotransduction by the Cdh5 complex in vascular endothelial cells is also known to cause local cytoskeletal remodeling, alter peripheral cell–cell junctions, and activate global signals that disrupt intercellular contacts [48]. Pmel is a type I single transmembrane glycoprotein that is expressed in the substantia nigra, pigmented melanocytes, and retinal pigment epithelium, and it also has an interesting role as a functional amyloid [49, 50]. Although no direct relationship between Pmel and gravitational response has been reported, it was shown that amyloid fibrils with a unique shape, different from those on the ground, formed in a μ‐g environment [51].…”

“…Pmel is a type I single transmembrane glycoprotein that is expressed in the substantia nigra, pigmented melanocytes, and retinal pigment epithelium, and it also TA B L E 1 List of proteins with similar serum level changes (p value [-log 10 ] > 1.3) in spaceflight mice with μ-g versus A1-g exposure and in HU versus control mice. has an interesting role as a functional amyloid [49,50]. Although no direct relationship between Pmel and gravitational response has been reported, it was shown that amyloid fibrils with a unique shape, different from those on the ground, formed in a μ-g environment [51].…”

Mutations inGPNMBassociated with Amyloid cutis dyschromica alter intracellular trafficking and processing of GPNMB

“…In contrast, C425 constitutes one of six highly-conserved Cysteine residues commonly found in Kringle domains. These cysteines form three disulfide bonds which are crucial for the correct folding of the domain (Chrystal et al 2021) (Figure 1B). Previous work has shown that GPNMB is post-translationally modified through Nglycosylation of its ectodomain, occurring in both the ER (precursor (P1) form) and trans-Golgi network (mature (M) form) (Hoashi et al 2010).…”

“…In contrast, C425 constitutes one of six highly-conserved Cysteine residues commonly found in Kringle domains. These cysteines form three disulfide bonds which are crucial for the correct folding of the domain (Chrystal et al 2021) (Figure 1B).…”