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Mutation near the binding interfaces at ?-hemoglobin stabilizing protein is highly pathogenic.

ABSTRACT: Aggregation of free alpha-hemoglobin proteins forms harmful reactive oxygen radicals during the development of normal erythroid cell, which can be prevented by a chaperone, alpha hemoglobin stabilizing protein (AHSP). Mutations at the AHSP gene may affect its interacting ability with other globin proteins. Various state-of-the-art tools have been extensively used to identify the most deleterious nsSNPs at the AHSP and their pathogenic effect during AHSP-globin interaction. Comprehensive analysis revealed that the V56G of the AHS protein is the most pathogenic amino acid substitution, agreed consistently and significantly (P=1.27E-13) by all the state-of-the-art tools (PROVEAN <-2.5, SIFT=0, SNAP2 >50, SNPs&GO >0.5, PolyPhen >0.5, FATHMM >0.6, PANTHER <-3, VEST P<0.05) and protein-protein interaction analysis. The V56G exists near the hot spot and was found to be the highly pathogenic and it forms an extra helix on mutation. The unchaperoned HBA2 and KLF1 proteins with the AHSP mutant (V56G) chains denote the non-interactive nature. Binding energies were significantly varied upon highly deleterious mutation at AHSP and/or HBA1 gene. The study endorses the mutated AHSP protein, p.val56Gly for detailed confirmatory wet lab analysis.

SUBMITTER: Borgio JF

PROVIDER: S-EPMC5095315 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Mutation near the binding interfaces at α-hemoglobin stabilizing protein is highly pathogenic.

Borgio Jesu Francis JF Al-Madan Mohammed S MS AbdulAzeez Sayed S

American journal of translational research 20161015 10

Aggregation of free alpha-hemoglobin proteins forms harmful reactive oxygen radicals during the development of normal erythroid cell, which can be prevented by a chaperone, alpha hemoglobin stabilizing protein (AHSP). Mutations at the <i>AHSP</i> gene may affect its interacting ability with other globin proteins. Various state-of-the-art tools have been extensively used to identify the most deleterious nsSNPs at the AHSP and their pathogenic effect during AHSP-globin interaction. Comprehensive a ...[more]

PMID: 27830006

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Project description:Enteroviruses are common agents of infectious disease that are spread by the fecal-oral route. They are readily inactivated by mild heat, which causes the viral capsid to disintegrate or undergo conformational change. While beneficial for the thermal treatment of food or water, this heat sensitivity poses challenges for the stability of enterovirus vaccines. The thermostability of an enterovirus can be modulated by the composition of the suspending matrix, though the effects of the matrix on virus stability are not understood. Here, we determined the thermostability of four enterovirus strains in solutions with various concentrations of NaCl and different pH values. The experimental findings were combined with molecular modeling of the protein interaction forces at the pentamer and the protomer interfaces of the viral capsids. While pH only had a modest effect on thermostability, increasing NaCl concentrations raised the breakpoint temperatures of all viruses tested by up to 20°C. This breakpoint shift could be explained by an enhancement of the van der Waals attraction forces at the two protein interfaces. In comparison, the (net repulsive) electrostatic interactions were less affected by NaCl. Depending on the interface considered, the breakpoint temperature shifted by 7.5 or 5.6°C per 100-kcal/(mol·Å) increase in protein interaction force.IMPORTANCE The genus Enterovirus encompasses important contaminants of water and food (e.g., coxsackieviruses), as well as viruses of acute public health concern (e.g., poliovirus). Depending on the properties of the surrounding matrix, enteroviruses exhibit different sensitivities to heat, which in turn influences their persistence in the environment, during food treatment, and during vaccine storage. Here, we determined the effect of NaCl and pH on the heat stability of different enteroviruses and related the observed effects to changes in protein interaction forces in the viral capsid. We demonstrate that NaCl renders enteroviruses thermotolerant and that this effect stems from an increase in van der Waals forces at different protein subunits in the viral capsid. This work sheds light on the mechanism by which salt enhances virus stability.

Dataset Information

Mutation near the binding interfaces at ?-hemoglobin stabilizing protein is highly pathogenic.

Publications

Mutation near the binding interfaces at α-hemoglobin stabilizing protein is highly pathogenic.

Similar Datasets

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