钴胺素
同型半胱氨酸尿
突变体
遗传学
错义突变
突变
点突变
生物
医学
基因
生物化学
维生素B12
氨基酸
蛋氨酸
作者
Rosa Passantino,Maria Rosalia Mangione,María Grazia Ortore,Maria Assunta Costa,Alessia Provenzano,Heinz Amenitsch,Raffaele Sabbatella,Caterina Alfano,Vincenzo Martorana,Silvia Vilasi
标识
DOI:10.1016/j.bbapap.2022.140793
摘要
The cblC disease is an inborn disorder of the vitamin B12 (cobalamin, Cbl) metabolism characterized by methylmalonic aciduria and homocystinuria. The clinical consequences of this disease are devastating and, even when early treated with current therapies, the affected children manifest symptoms involving vision, growth, and learning. The illness is caused by mutations in the gene codifying for MMACHC, a 282aa protein that transports and transforms the different Cbl forms. Here we present data on the structural properties of the truncated protein p.R132X resulting from the c.394C > T mutation that, along with c.271dupA and c.331C > T, is among the most common mutations in cblC. Although missing part of the Cbl binding domain, p.R132X is associated to late-onset symptoms and, therefore, it is supposed to retain residual function. However, to our knowledge structural-functional studies on c.394C > T mutant aimed at verifying this hypothesis are still lacking. By using a biophysical approach including Circular Dichroism, fluorescence, Small Angle X-ray Scattering, and Molecular Dynamics, we show that the mutant protein MMACHC-R132X retains secondary structure elements and remains compact in solution, partly preserving its binding affinity for Cbl. Insights on the fragile stability of MMACHC-R132X-Cbl are provided.
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