Human
Interferon-Beta (PDB ID: 1AU1) from Homo Sapiens
Created By Sung W Lee
Human interferon beta (PDB ID = 1AU1) classifies as interferon (IFNs), which is the protein to defend the cells from various viruses (9). To protect cells from virus, IFNs do two different jobs: interfere virus growth and alert the cell of virus invasion. Once virus invades the cells, IFNs delay the virus’s action by slowing down the growth of infected cells and give the neighbor cells the signal to produce antibodies for viral defense. Two virologists, Alick Isaacs from Great Britain and Jean Lindenmann from Switzerland identified the interferons in 1957 and sorted into three categories based on their size and shape: alpha, beta, and gamma (2). Each of IFNs may engage receptor components in a different way, and it leads the differences in biological activities observed for different IFN subtypes. Therefore, it is important to study different types of interferons, including human interferon beta to specify their roles. If scientist can figure out how each IFNs works, IFNs will be the perfect treatment for fighting viral infections (1).
Two
different ways were used to analyze human interferon beta: researching information
about human IFN beta from Protein Data Bank (PDB) and Expasy and comparing the
protein with other proteins which have similar structure using BLAST and Dali
server.
Human interferon beta is a protein that consists of single polymer. Its molecular weight and isoelectric point are 40036.15 Da and 9.02 respectively (8). In single polymer of human IFN beta, two identical subunits, chain A and chain B, exist. The secondary structure of human IFN beta is composed of only three elements; alpha helices, 3/10-helices and random coils. Human IFN beta has three associated ligands; beta-D-glucose, 6-deoxy-alpha-d-glucose, and zinc ion. Beta-D-glucose is a primary source of energy for living organism, but in human IFN beta, it forms hydrogen bonds with the residue Asn-80 and Thr-82 in subunit chain A. 6-deloxy-alpha-D-glucose also forms hydrogen bond with the residue Asn-86 in subunit chain A. Zinc ion’s function has an important role in the inhibition of potentially destructive immune reaction against the T lymphocytes, and in the predisposing inflammatory response of multiple sclerosis. It is also an antioxidant which protests the cell membranes and myelin (5). Each subunit chain of human IFN beta is composed of 166 amino acid residues (9). Among them, a number of residues in human IFN beta have their own roles, and some residues contribute to the protein’s functions. Non-covalent interactions such as hydrogen bond and hydrophobic interaction happen between residues to stabilize the structure. For example, hydrogen bonds are formed between Gln-10 and Gln-94, between Ser-118 and Thr-58. The residues such as Phe-70, Phe-154, Trp-79, and Trp-143 also form hydrophobic interaction each other to stabilize the core of the molecule. On the other hand, without interaction with other residue, Asn-80 has a role as a single glycosylation site which is involved in solubility and stability of the protein so that the glycosylated IFN-beta can gives higher anti-viral activity (6). Glu-43 has been identified as an antigenic epitope with the residues 41-42 and 46, and they have a role to bind antibodies and give an entire molecule function to fight against viral infection (1). Due to its function to fight against viral infections effectively, human IFN beta is used as treatment for multiple sclerosis (MS). Avonex and Rebif, which use the subunit chain A of human IFN beta and Betaseron and Extavia which use the subunit chain B of human IFN beta are approved by FDA and sold (3).
The comparison human IFN beta with human IFNa2-IFNAR ternary complex (PDB ID = 3SE3) gave more intuition to understand the structure of human IFN beta. The criteria to choose the comparison protein are E value and Z score. E value is determined by comparing the sequence of a certain protein to other proteins and assigning gaps. The lower E value is, the higher similarity in sequences between proteins, and a score below 0.5 in E value indicates high similarity between proteins. Z score shows how much the proteins have similar folds; a score above 2 in Z score means the proteins have similar folds. To find both E value and Z score, PSI-blast and Dali server are used respectively. PSI-blast is a program used to find proteins with similar primary structure to a protein query (4). On the other hand, Dali server is a program used to compare tertiary structures of proteins and calculate the differences in intramolecular distances (7). With the charts from PSI-blast and Dali server, human IFNa2-IFNAR ternary complex with E value 1×10-22 (4) and Z score 16.3 (7). As shown in low E value and high Z score, human IFNa2-IFNAR ternary complex is composed of 3 subunits; interferon alpha/beta receptor 1, interferon alpha/beta receptor 2, and interferon alpha 2b. Among them, the best matched part is interferon alpha 2b as subunit chain B. Two interferon alpha/beta receptors consist of large amount of beta strand for their second structure while interferon alpha 2b has only alpha helices, 3/10 helices, and random coils just like human interferon beta (9). However, comparing both human IFN beta and human IFN alpha from human IFNa2-IFNAR ternary complex with their sequences, the data shows significant different amino acids arrangement (7). Due to the similarity of structures shown in the superimposition, IFN alpha from human IFNa2-IFNAR ternary complex also interferes virus growth and alerts the cell of virus invasion just like human IFN beta, but IFN alpha that has different amino acids arrangement binds to different receptor and interferes the growth of different types of viruses.