User:Cprice37/Histone-like nucleoid-structuring protein

Lead

Histone-like nucleoid-structuring protein (H-NS), is one of twelve nucleoid-associated proteins (NAPs) whose main function is the organization of genetic material, including the regulation of gene expression via xenogeneic silencing. H-NS is characterized by an N-terminal domain (NTD) consisting of two dimerization sites, a linker region that is unstructured and a C-terminal domain (CTD) that is responsible for DNA-binding. This protein provides essential nucleoid compaction and regulation of genes, mainly silencing. At specific cell conditions, such as change in temperature, H-NS can be dissociated from the DNA duplex, allowing for transcription by RNA polymerase, and in specific regions lead to pathogenic cascades.

Structure

Gene repression by H-NS is caused by the formation of oligomers. These oligomers form due to dimerization of two sites in the N-terminal domain (NTD). In bacterial species like Salmonella typhimurium, the NTD of H-NS contains dimerization sites in helices alpha 1, alpha 2 and alpha 3. Alpha helices 3 and 4 are then responsible for creating the superhelical structure of H-NS by forming

Figure 3: This figure portrays the oligomerization occuring in the alpha helices of the NTD (black, teal and magenta) in H-NS (and homologues) forming what is known as a "handshake topology" and an estimated view of how the CTD (green and orange) binds to DNA.

The C-terminal domain (CTD) is also known as the DNA-binding domain. H-NS NTD's oligomerize with each other while the CTD binds to specific regions of DNA containing a specific topology called a TpA step.

Function (Mechanism)

A major function of H-NS is to influence DNA topology. H-NS is responsible for formation of nucleofilaments along the DNA and DNA-DNA bridges (refer to Figure 1). H-NS is known as a passive DNA bridger, meaning that it binds two distant segments of DNA and remains stationary, forming a loop. This DNA loop formation allows H-NS to control gene expression. Relief of suppression by H-NS can be achieved by the binding of another protein, or by changes in DNA topology which can occur due to changes in temperature and osmolarity, for example.

The C-Terminal Domain of H-NS shows high affinity for regions in DNA that are rich in Adenine and Thymine and present in a hook-like motif in a minor groove. The base stacking present in this AT rich region of the DNA allows for minor widening of the minor groove that is preferential for binding. This is a common feature seen in horizontally acquired genes.

H-NS can also interact with other proteins and influence their function, for example it can interact with the flagellar motor protein FliG to increase its activity.

Clinical Significance

H-NS has a conserved role in the pathogenicity of gram-negative bacteria including Shigella spp. and Escherichia coli. It is implicated in the transcription of the virF gene leading to bacillary dysentery, a disease affecting children mainly seen in developing countries. These two bacterial species contain a virulence plasmid that is responsible for invasion of host cells and is regulated by H-NS.