المؤلفون: Bouke P. C. Hazenberg, Stefan Schoenland, Bernd Reif, Tejaswini Pradhan, Christian Haupt, M. Faendrich, J. Schoenfelder, Johan Bijzet, Ute Hegenbart, P. B. Pfeiffer

المساهمون: Translational Immunology Groningen (TRIGR)

المصدر: Amyloid, 28(4), 243-251. Taylor & Francis Ltd

مصطلحات موضوعية: PROTEINS, medicine.medical_treatment, proteolytic stability, macromolecular substances, Fibril, prion, Amyloid disease, Internal Medicine, medicine, Serum amyloid A, protein misfolding, immunoglobulin light chain, GLYCOSAMINOGLYCANS, chemistry.chemical_classification, Protease, biology, Chemistry, serum amyloid A, Amyloid fibril, TRANSTHYRETIN, In vitro, POLYMORPHISM, Amino acid, Transthyretin, Amyloid structure, biology.protein, Biophysics, Protein folding, Ex vivo

الوصف: Several studies recently showed that ex vivo fibrils from patient or animal tissue were structurally different from in vitro formed fibrils from the same polypeptide chain. Analysis of serum amyloid A (SAA) and Aβ-derived amyloid fibrils additionally revealed that ex vivo fibrils were more protease stable than in vitro fibrils. These observations gave rise to the proteolytic selection hypothesis that suggested that disease-associated amyloid fibrils were selected inside the body by their ability to resist endogenous clearance mechanisms. We here show, for more than twenty different fibril samples, that ex vivo fibrils are more protease stable than in vitro fibrils. These data support the idea of a proteolytic selection of pathogenic amyloid fibril morphologies and help to explain why only few amino acid sequences lead to amyloid diseases, although many, if not all, polypeptide chains can form amyloid fibrils in vitro.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e229dee1268b3cc10a97beb6344d5b95Test
https://doi.org/10.1080/13506129.2021.1960501Test

المؤلفون: Christian Haupt, Marcus Fändrich

المصدر: Trends in Biotechnology. 32:513-520

مصطلحات موضوعية: Models, Molecular, Amyloid, Peptide inhibitor, Bioengineering, Amyloidosis, Biology, Protein aggregation, Protein Engineering, Systemic amyloidosis, Amyloid disease, Molecular recognition, Biochemistry, Clinical diagnosis, Humans, Protein folding, Protein Binding, Biotechnology

الوصف: The aberrant self-assembly of polypeptide chains into amyloid structures is a common phenomenon in several neurodegenerative diseases, systemic amyloidosis, and 'normal' aging. Improvements in laboratory-scale detection of these structures, their clinical diagnosis, and the treatment of disease likely depend on the advent of new molecules that recognize particular states or induce their clearance in vivo. This review will describe what biotechnology can do to generate proteinaceous amyloid-binders, explain their molecular recognition mechanisms, and summarize possibilities to functionalize further these ligands for specific applications.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3744ed56ad8879aa5830e8e4adb7cbc0Test
https://doi.org/10.1016/j.tibtech.2014.08.004Test

المؤلفون: Olga Gursky, Donald L. Gantz, Shobini Jayaraman, Christian Haupt

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 114(32)

مصطلحات موضوعية: 0301 basic medicine, Amyloid, Proteolysis, Fibril, Protein Structure, Secondary, 03 medical and health sciences, Amyloid disease, Mice, AA amyloidosis, medicine, Animals, Serum amyloid A, Serum Amyloid A Protein, Multidisciplinary, medicine.diagnostic_test, Chemistry, Amyloidosis, Intracellular Membranes, Hydrogen-Ion Concentration, medicine.disease, 030104 developmental biology, Biochemistry, PNAS Plus, Protein Multimerization, Lysosomes

الوصف: Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5-4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5-4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::62b3b95716c8bd4e7299b6a8aace30e9Test
https://pubmed.ncbi.nlm.nih.gov/28743750Test