@article{17331, abstract = {Amyloidosis are a group of diseases in which soluble proteins aggregate and deposit in fibrillar conformation extracellularly in tissues. The effectiveness of therapeutic strategies depends on the specific protein involved, being crucial to accurately determine its nature. Moreover, following the diagnosis, the search for the mutation within relatives allows the clinical advice. Here we report the precise diagnosis and explored the possible reasons of the structural pathogenicity for a renal amyloidosis related to a fibrinogen Aα-chain variant. Whole-exome sequencing and GATK calling pipeline were leveraged to characterize the protein variant present in a patient with kidney failure. Bioinformatics strategies were applied to suggest potential explanations of the variants aggregation. Our pipeline allowed the identification of a single-point variant of fibrinogen Aα-chain, which opened the possibility of curative transplantation. In silico structural analysis suggested that the pathogenicity of the variant may be attributed to a heightened susceptibility to yield a peptide prone to deposit as an oligomer with a β-sheet structure. Exploiting the comprehensive coverage of whole-genome sequencing, we managed to fill a vacant stage in the diagnosis of hereditary amyloidosis and to stimulate the advancement in biomedicine.}, author = {Cattaneo, Elizabeth R and Gisonno, Romina A and Abba, Martín C and Santana, Marianela and Rosú, Silvana A and Nucifora, Elsa and Aguirre, María A and Giordani, María C and Tricerri, M. Alejandra and Ramella, Nahuel A}, issn = {1097-0134}, journal = {Proteins: Structure, Function and Bioinformatics}, number = {12}, pages = {1366--1374}, publisher = {Wiley}, title = {{Hereditary amyloidosis: Insights into a fibrinogen A variant protein}}, doi = {10.1002/prot.26732}, volume = {92}, year = {2024}, } @article{15268, abstract = {Apolipoprotein A‐I (apoA‐I) has a key function in the reverse cholesterol transport. However, aggregation of apoA‐I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural consequences introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA‐I. We combined evolutionary studies, in silico mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation‐prone regions (APRs) present in apoA‐I. Sequence analysis demonstrated that among the four amyloidogenic regions described for human apoA‐I, only two (APR1 and APR4) are evolutionary conserved across different species of Sarcopterygii. Moreover, stability analysis carried out with the FoldX engine showed that APR1 contributes to the marginal stability of apoA‐I. Structural properties of full‐length apoA‐I models suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Compared to silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of amyloid mutations showed evidence of a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the alpha‐helix bundle with the concomitant exposure of APR1 to the solvent, suggesting an insight into the early steps involved in its aggregation. Our findings highlight APR1 as a relevant component for apoA‐I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of this region.}, author = {Gisonno, Romina A. and Masson, Tomas and Ramella, Nahuel A. and Barrera, Exequiel E. and Romanowski, Víctor and Tricerri, M. Alejandra}, issn = {1097-0134}, journal = {Proteins: Structure, Function, and Bioinformatics}, keywords = {Molecular Biology, Biochemistry, Structural Biology}, number = {1}, pages = {258--269}, publisher = {Wiley}, title = {{Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior}}, doi = {10.1002/prot.26217}, volume = {90}, year = {2022}, } @article{3978, abstract = {Evaluating the quality of experimentally determined protein structural models is an essential step toward identifying potential errors and guiding further structural refinement. Herein, we report the use of proton local density as a sensitive measure to assess the quality of nuclear magnetic resonance (NMR) structures. Using 256 high-resolution crystal structures with protons added and optimized, we show that the local density of different proton types display distinct distributions. These distributions can be characterized by statistical moments and are used to establish local density Z-scores for evaluating both global and local packing for individual protons. Analysis of 546 crystal structures at various resolutions shows that the local density Z-scores increase as the structural resolution decreases and correlate well with the ClashScore (Word et al. J Mol Biol 1999;285(4):1711-1733) generated by all atom contact analysis. Local density Z-scores for NMR structures exhibit a significantly wider range of values than for X-ray structures and demonstrate a combination of potentially problematic inflation and compression. Water-refined NMR structures show improved packing quality. Our analysis of a high-quality structural ensemble of ubiquitin refined against order parameters shows proton density distributions that correlate nearly perfectly with our standards derived from crystal structures, further validating our approach. We present an automated analysis and visualization tool for proton packing to evaluate the quality of NMR structures.}, author = {Ban, Yih and Rudolph, Johannes and Zhou, Pei and Edelsbrunner, Herbert}, issn = {1097-0134}, journal = {Proteins: Structure, Function and Bioinformatics}, number = {4}, pages = {852 -- 864}, publisher = {Wiley-Blackwell}, title = {{Evaluating the quality of NMR structures by local density of protons}}, doi = {10.1002/prot.20811}, volume = {62}, year = {2006}, }