Co-aggregation and secondary nucleation in the life cycle of human prolactin/galanin functional amyloids

Abstract

Synergistic-aggregation and cross-seeding by two different proteins/peptides in the amyloid aggregation are well evident in various neurological disorders including Alzheimer’s disease. Here, we show co-storage of human Prolactin (PRL), which is associated with lactation in mammals, and neuropeptide galanin (GAL) as functional amyloids in secretory granules (SGs) of the female rat. Using a wide variety of biophysical studies, we show that irrespective of the difference in sequence and structure, both hormones facilitate their synergic aggregation to amyloid fibrils. Although each hormone possesses homotypic seeding ability, a unidirectional cross-seeding of GAL aggregation by PRL seeds and the inability of cross seeding by mixed fibrils suggest tight regulation of functional amyloid formation by these hormones for their efficient storage in SGs. Further, the faster release of functional hormones from mixed fibrils compared to the corresponding individual amyloid, suggests a novel mechanism of heterologous amyloid formation in functional amyloids of SGs in the pituitary.

Probing the Biosafety of Implantable Artificial Secretory Granules for the Sustained Release of Bioactive Proteins

“…These cores further recruit the monomeric counterpart to grow into mature amyloid fibrils, eventually reaching a steady-state equilibrium between the fibrils and monomeric proteins. 64 Based on this equilibrium, the protein storage as an amyloid depot is also able to release the functional monomeric proteins upon dilution. 64 Mimetic versions of these natural systems have been recently developed, which has resulted in promising delivery systems, fully functional and operational in different experimental settings in vitro and in vivo.…”

“…64 Based on this equilibrium, the protein storage as an amyloid depot is also able to release the functional monomeric proteins upon dilution. 64 Mimetic versions of these natural systems have been recently developed, which has resulted in promising delivery systems, fully functional and operational in different experimental settings in vitro and in vivo. 24,26,42,65 The protein is then selfcontained in vitro when exposed to cationic Zn and self-delivered in vivo, upon administration, when the metal is diluted in the physiological medium.…”

“…This mechanism is the basis of the human endocrine system that stores and releases a diversity of peptide hormones. − Many secretory hormones from the mammalian endocrine system form functional amyloids in secretory granules. − Importantly, irrespective of their sequence and structure, they aggregate as amyloid fibrils. , Thus, protein aggregation and amyloid formation follows a polymerization mechanism where protein or peptide species slowly associate to form aggregation competent nuclei. These cores further recruit the monomeric counterpart to grow into mature amyloid fibrils, eventually reaching a steady-state equilibrium between the fibrils and monomeric proteins . Based on this equilibrium, the protein storage as an amyloid depot is also able to release the functional monomeric proteins upon dilution …”

“…These cores further recruit the monomeric counterpart to grow into mature amyloid fibrils, eventually reaching a steady-state equilibrium between the fibrils and monomeric proteins . Based on this equilibrium, the protein storage as an amyloid depot is also able to release the functional monomeric proteins upon dilution …”

Charge and hydrophobicity of amyloidogenic protein/peptide templates regulate the growth and morphology of gold nanoparticles

“…Amyloids are highly ordered protein/peptide aggregates with cross-β-sheet rich structures 17 often associated with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. 18 Apart from their implications in diseases, amyloids called "functional amyloids" have also evolved for native biological functions in hosts, [19][20][21] such as curli fibrils in E. coli. 22 Previously, amyloid fibrils were used for designing biomaterials due to their unique properties such as high tensile strength, thermal and pH stability.…”