Proteins from the Human Gut Microbiota

One of the main areas of focus of JCSG research was the human microbiota, which is the community of commensal, symbiotic, and pathogenic microorganisms that live in and on the human body. It is estimated that there are more than 10x more microbes living in and on a human host than there are human cells. In the human gut alone, it is estimated that there are ~500 microbial species present.

Research has increasingly shown that these microorganisms play important roles in human health and disease. They help maintain human health by aiding in nutrient absorption, keeping harmful pathogens in check, and promoting the development of the immune system. And the absence or imbalance of these microbes could contribute to diseases such as diabetes, obesity, inflammatory diseases, and some cancers.

One genus of bacteria from the human microbiota that the JCSG focused on is Bacteroides, which is a predominant member of the human distal gut that plays an important role in the breakdown and absorption of nutrients from the foods that we eat. I determined the 3D structures of several proteins from this genus, two of which were further analyzed in-depth and described below.

BT2081 from Bacteroides thetaiotaomicron

One of these proteins is BT2081 from Bacteroides thetaiotaomicron (PDB ID 3hbz, structure #3 in Table 1), analysis of which revealed that it represents the first structure from a new protein family that may play a role in carbohydrate metabolism in the human distal gut microbiota (Figure 1a). Conserved amino acid residues in the putative carbohydrate-binding pocket (Figure 1b) suggest the possibility of BT2081acting as a glycoside hydrolase, an enzyme which catalyzes the cleavage of the glycosidic bonds in monosaccharide, disaccharides and polysaccharides into their constituent sugar units. The full journal article detailing our findings can be found here.

Figure 1. (a) 3D structure of BT2081 as determined by X-ray crystallography to 2.05 Å resolution. BT2081 comprises two distinct domains: (i) an N-terminal domain (green) that adopts a β-sandwich immunoglobulin (Ig) like fold and (ii) a C-terminal domain (purple) that adopts a β-sandwich jelly-roll fold. (b) the C-terminal domain contains a pocket that is lined by amino acid residues suggestive of a carbohydrate-binding pocket. An arrow indicates the pocket entrance. The residues that line the pocket are highlighted in stick representation and are color-coded according to type as follows: aromatic, green; hydrophobic, light green; polar, lilac; acidic, red; and basic, blue.

BVU_4064 from Bacteroides vulgatus

The second protein is BVU_4064 from Bacteroides vulgatus (PDB ID 3kog, structure #11 in Table 1).  The structure of BVU_4064 (Figure 2) consists of two distinct domains: an 80-residue N-terminal domain that adopts a pre-albumin-like fold and a 130-residue beta-strand-rich C-terminal domain. Structural comparisons reveal that the N-terminal domain is structurally similar to domains found in bacterial cell-adhesion proteins, which suggests that this domain may function as an extracellular adhesion or carbohydrate-binding module. The C-terminal domain is structurally similar to the β-pore-forming domain of bacterial toxins, suggesting that this domain could play a role in either lipid or carbohydrate interactions. An ordered histidine-rich region is also present at the C-terminus and is speculated to potentially mediate a specific interaction either with metals or charged moieties in the bacterial cell wall. The analysis of this structure suggests that this protein may be involved in adhesive and carbohydrate interactions at the cell-surface/extracellular matrix. The full journal article detailing our findings can be found here.

Figure 2. 3D structure of the N-terminally truncated BVU_4064 as determined by X-ray crystallography to 1.85 Å resolution. BVU_4064 consists of two distinct domains: (i) an 80-residue N-terminal domain (blue) that adopts a pre-albumin-like fold and (ii) a 130-residue beta-strand-rich C-terminal domain (orange). An ordered histidine-rich region (labeled with arrow) is also present at the C-terminus.

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