RESUMEN
The C-terminal domain of SARS-CoV main protease (Mpro-C) can form 3D domain-swapped dimer by exchanging the α1-helices fully buried inside the protein hydrophobic core, under non-denaturing conditions. Here, we report that Mpro-C can also form amyloid fibrils under the 3D domain-swappable conditions in vitro, and the fibrils are not formed through runaway/propagated domain swapping. It is found that there are positive correlations between the rates of domain swapping dimerization and amyloid fibrillation at different temperatures, and for different mutants. However, some Mpro-C mutants incapable of 3D domain swapping can still form amyloid fibrils, indicating that 3D domain swapping is not essential for amyloid fibrillation. Furthermore, NMR H/D exchange data and molecular dynamics simulation results suggest that the protofibril core region tends to unpack at the early stage of 3D domain swapping, so that the amyloid fibrillation can proceed during the 3D domain swapping process. We propose that 3D domain swapping makes it possible for the unpacking of the amyloidogenic fragment of the protein and thus accelerates the amyloid fibrillation process kinetically, which explains the well-documented correlations between amyloid fibrillation and 3D domain swapping observed in many proteins.
Asunto(s)
Amiloide/química , Amiloide/metabolismo , Amiloidosis/metabolismo , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Dominios Proteicos/fisiología , Amiloidosis/genética , Proteasas 3C de Coronavirus/genética , Dimerización , Disulfuros/química , Disulfuros/metabolismo , Cinética , Modelos Moleculares , Simulación de Dinámica Molecular , Mutación , Polimerizacion , Conformación Proteica en Hélice alfa , Dominios Proteicos/genética , Pliegue de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , TemperaturaRESUMEN
Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.
Asunto(s)
Artritis/metabolismo , Enfermedades Cardiovasculares/metabolismo , Osteoporosis/metabolismo , Prealbúmina/metabolismo , Amiloide/química , Amiloide/metabolismo , Amiloidosis/metabolismo , Animales , Humanos , Estrés Oxidativo , Prealbúmina/química , Conformación Proteica , Estabilidad ProteicaRESUMEN
Severe coronavirus disease 2019 (COVID-19) infection leads to multifactorial acute respiratory distress syndrome (ARDS), with little therapeutic success. The pathophysiology associated with ARDS or post-ARDS is not yet well understood. We hypothesize that amyloid formation occurring due to protein homeostasis disruption can be one of the complications associated with COVID-19-induced-ARDS.