Modulating functional amyloid formation via alternative splicing of the premelanosomal protein PMEL17

Dean, Dexter N.; Lee, Jennifer C.

doi:10.1074/jbc.ra120.013012

Cited by 13 publications

(14 citation statements)

References 35 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggests that prion cross-infectivity is generally adjusted through a templateassisted mechanism that depends on strain-relevant structural conformation compatibility [169,227]. Unilateral cross-aggregation templating by alternative spliceoforms or naturally occurring glycosaminoglycans is an additional conformation-specific strategy used for the formation of functional amyloid in higher organisms [228,229].…”

Section: Hetero-aggregation In Functional Amyloidsmentioning

confidence: 99%

Heterotypic interactions in amyloid function and disease

et al. 2021

View full text Add to dashboard Cite

Amyloid aggregation results from the self‐assembly of identical aggregation‐prone sequences into cross‐beta‐sheet structures. The process is best known for its association with a wide range of human pathologies but also as a functional mechanism in all kingdoms of life. Less well elucidated is the role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease. We here review current data with a focus on neurodegenerative amyloid‐associated diseases. Evidence indicates that heterotypic interactions occur in a wide range of amyloid processes and that these interactions modify fundamental aspects of amyloid aggregation including seeding, aggregation rates and toxicity. More work is required to understand the mechanistic origin of these interactions, but current understanding suggests that both supersaturation and sequence‐specific binding can contribute to heterotypic amyloid interactions. Further unravelling these mechanisms may help to answer outstanding questions in the field including the selective vulnerability of cells types and tissues and the stereotypical spreading patterns of amyloids in disease.

show abstract

Section: Hetero-aggregation In Functional Amyloidsmentioning

confidence: 99%

Heterotypic interactions in amyloid function and disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Given the epidemiological context of melanoma among PD patients, we chose cross-seeding experiments where preformed α-syn fibrils, which accumulate in PD, were added to soluble Pmel17 RPT (residues 315 to 444), an essential domain for fibril formation in melanosomes (11). α-Syn and RPT fibril seeds were generated by continuous agitation in pH 6 buffer, mimicking the acidic conditions of the melanosome as previously described (12). Visualization by transmission electron microscopy (TEM) showed a mixture of rod-like (arrows) and twisted (brackets) fibril morphologies for α-syn ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Arrow indicates a distinctive feature (1,250 cm −1 ) in self-seeded RPT fibrils, that is less prominent in cross-seeded and α-syn fibrils. Self-seeded RPT data are reproduced from previous work ( 12 ). ( G ) Schematic representation of cathepsin L limited digestion, where lines represent cleavage sites ( Top ) and peptide fragments ( Bottom ) observed in both self-seeded and cross-seeded RPT fibrils.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Defining an amyloid link Between Parkinson’s disease and melanoma

Dean

Lee

2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

An epidemiological connection exists between Parkinson’s disease (PD) and melanoma. α-Synuclein (α-syn), the hallmark pathological amyloid observed in PD, is also elevated in melanoma, where its expression is inversely correlated with melanin content. We present a hypothesis that there is an amyloid link between α-syn and Pmel17 (premelanosomal protein), a functional amyloid that promotes melanogenesis. Using SK-MEL 28 human melanoma cells, we show that endogenous α-syn is present in melanosomes, the organelle where melanin polymerization occurs. Using in vitro cross-seeding experiments, we show that α-syn fibrils stimulate the aggregation of a Pmel17 fragment constituting the repeat domain (RPT), an amyloidogenic domain essential for fibril formation in melanosomes. The cross-seeded fibrils exhibited α-syn−like ultrastructural features that could be faithfully propagated over multiple generations. This cross-seeding was unidirectional, as RPT fibrils did not influence α-syn aggregation. These results support our hypothesis that α-syn, a pathogenic amyloid, modulates Pmel17 aggregation in the melanosome, defining a molecular link between PD and melanoma.

show abstract

“…Cross-seeding between family members as a possible means to regulate functional amyloid assembly has not yet been established in mammals. However, recent studies showed that alternative splicing within the amyloidogenic repeat domain of human PMEL, which forms an amyloid integral for melanin synthesis, resulted in an isoform that served as a nucleator to facilitate the amyloidogenesis of the longer PMEL form ( 19 ). These studies revealed a different mechanism to achieve the same result of a controlled nucleated polymerization as in E. coli .…”

mentioning

confidence: 99%

Cross-seeding between the functional amyloidogenic CRES and CRES3 family members and their regulation of Aβ assembly

Quynh

Hewetson

Borcik

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Accumulating evidence shows that amyloids perform biological roles. We previously showed that an amyloid matrix composed of four members of the CRES subgroup of reproductive family 2 cystatins is a normal component of the mouse epididymal lumen. The cellular mechanisms that control the assembly of these and other functional amyloid structures, however, remain unclear. We speculated that cross-seeding between CRES members could be a mechanism to control the assembly of the endogenous functional amyloid. Herein we used thioflavin T assays and negative stain transmission electron microscopy to explore this possibility. We show that CRES3 rapidly formed large networks of beaded chains that possessed the characteristic cross-β reflections of amyloid when examined by X-ray diffraction. The beaded amyloids accelerated the amyloidogenesis of CRES, a less amyloidogenic family member, in seeding assays during which beads transitioned into films and fibrils. Similarly, CRES seeds expedited CRES3 amyloidogenesis, although less efficiently than the CRES3 seeding of CRES. These studies suggest that CRES and CRES3 hetero-oligomerize and that CRES3 beaded amyloids may function as stable preassembled seeds. The CRES3 beaded amyloids also facilitated assembly of the unrelated amyloidogenic precursor Aβ by providing a surface for polymerization though, intriguingly, CRES3 (and CRES) monomer/early oligomer profoundly inhibited Aβ assembly. The cross-seeding between the CRES subgroup members is similar to that which occurs between bacterial curli proteins suggesting that it may be an evolutionarily conserved mechanism to control the assembly of some functional amyloids. Further, interactions between unrelated amyloidogenic precursors may also be a means to regulate functional amyloid assembly.

show abstract

Modulating functional amyloid formation via alternative splicing of the premelanosomal protein PMEL17

Cited by 13 publications

References 35 publications

Heterotypic interactions in amyloid function and disease

Heterotypic interactions in amyloid function and disease

Defining an amyloid link Between Parkinson’s disease and melanoma

Cross-seeding between the functional amyloidogenic CRES and CRES3 family members and their regulation of Aβ assembly

Contact Info

Product

Resources

About