The IFNA2 mutation p.Ala120Thr substitutes hydrophobic alanine with hydrophilic threonine, altering the hydrophobic nature of that region. Our modeling further suggests that a hydrogen bond would be formed between the newly introduced OH of Thr120 and the main chain carbonyl oxygen at the adjacent Asn116. Residue 120 is located at the C-terminus of helix C. The substitution at this position may affect the conformation
of helix C and subsequently trigger movement of the connected loop region. A recently released crystal structure of IFN α-5 complexed with IFN-α/β binding protein Crenolanib supplier C12R (PDB code: 3OQ3)18 has demonstrated that helix C is needed for the interaction between IFN α-5 and the binding protein. The key role of residue 120 in helix C for partner protein binding is also supported by the crystal structure of human growth hormone with its receptor,19 which has a similar structure. Therefore, a mutation at 120 from alanine to threonine may affect Napabucasin in vivo the interaction of IFNA2 with its receptor. In addition, in the wildtype protein the neighboring residue Cys121 forms a disulfide bridge with Cys24 (Cys24-Cys121) between helices A and C. The mutation at residue 120, therefore, may perturb the disulfide bridge and subsequently the structure of helix A (Fig. 2A). The NLRX1 p.Arg707Cys
variant also occurs at a highly conserved residue. The crystal structure of the C-terminal fragment of human NLRX1 shows that Arg707 is located on the leucine-rich-repeat 1(LRR1) region between a β strand and an α helix. The substitution of a large, basic arginine by a medium-sized and polar cysteine introduces a significant change in electrostatic potential around that exposed region (Fig. 2B). Consequently, this may have impact
on the activity of the protein. The C2 variant p.Glu318Asp is located on the hydrophilic side of the α helix (Fig. 2C). The model suggests that this substitution is not likely to influence the intramolecular interaction significantly. 上海皓元 However, whether or not this site could affect interactions with other proteins is unknown. Immunohistochemistry with antihuman wildtype TMEM2 antibodies in healthy liver sections from 12 individuals detected strong, discrete, and granular cytoplasmic staining. The staining was further replicated with a different anti-TMEM2 antibody in liver sections from six additional individuals (Fig. 3A). Real-time PCR showed that the CHB liver tissues and HBV genome-containing HepG2.2.15 cell line expressed TMEM2 mRNA at reduced levels compared with healthy liver tissues (Fig. 3B), as did HepG2 cells devoid of the HBV genome (Fig. 3C) (P = 0.022 and 0.0036, respectively). Western blotting revealed reduced protein expression in HBV genome-containing HepG2.2.15 cell line when compared with HepG2 cells devoid of the HBV genome (Fig. 3D). We have identified four rare missense mutations associated with CHB.
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