Probing The Non-Generalized Amyloid Inhibitory Mechanism Of Hydrophobic Chaperone.

07:00 EST 14th January 2020 | BioPortfolio

Summary of "Probing The Non-Generalized Amyloid Inhibitory Mechanism Of Hydrophobic Chaperone."

Increasing prevalence of protein misfolding disorders urges the search for effective therapies. Although, several anti-aggregation molecules have been identified but their molecular process of aggregation and clinical trials are underway. Present study is focused on the mechanism through which phenyl butyrate (PB), a chemical chaperone, triggers inhibition of human serum albumin (HSA) fibrillation. Turbidity and rayleigh light scattering (RLS) measurements reveal marked presence of aggregates in HSA that were confirmed as amyloid fibrils by thioflavin T (ThT) and congo red (CR) and were subsequently inhibited by PB in dose dependent manner. ThT fluorescence kinetics reveals a decrease in apparent rate constant, Kapp in presence of PB without triggering lag phase in HSA suggesting PB's interference with elongation phase. Dynamic light scattering (DLS) results display reduction in aggregate size in presence of PB. Isothermal titration calorimetry (ITC) data reveals strong binding of PB at site II both at 25 ᵒC (Kb≈1.94×105 M-1) and 65ᵒC (Kb≈2.90×104 M-1), mediated by hydrogen bonding. Overall, our finding establishes that PB stabilizes partially unfolded HSA molecules through hydrogen bonding, thereby preventing establishment of hydrogen bonds between them, hindering their progression into amyloid fibrils. This is in contrast to its chaperone effect manifested with other proteins.


Journal Details

This article was published in the following journal.

Name: ACS chemical neuroscience
ISSN: 1948-7193


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Medical and Biotech [MESH] Definitions

A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.

A heterogeneous group of sporadic or familial disorders characterized by AMYLOID deposits in the walls of small and medium sized blood vessels of CEREBRAL CORTEX and MENINGES. Clinical features include multiple, small lobar CEREBRAL HEMORRHAGE; cerebral ischemia (BRAIN ISCHEMIA); and CEREBRAL INFARCTION. Cerebral amyloid angiopathy is unrelated to generalized AMYLOIDOSIS. Amyloidogenic peptides in this condition are nearly always the same ones found in ALZHEIMER DISEASE. (from Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., 2005)

Proteins that form the core of amyloid fibrils. For example, the core of amyloid A is formed from amyloid A protein, also known as serum amyloid A protein or SAA protein.

Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.

A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.

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