Immunoglobulin-fold containing bacterial adhesins: Molecular and structural perspectives in host tissue colonization and infection

Immunoglobulin (Ig) domains are one of the most widespread protein domains encoded by the human genome and are present in a large array of proteins with diverse biological functions. These Ig domains possess a central structure, the immunoglobulin fold, which is a sandwich of two β sheets, each made up of anti-parallel β strands, surrounding a central hydrophobic core. Apart from humans, proteins containing Ig-like domains are also distributed in a vast selection of organisms including vertebrates, invertebrates, plants, viruses and bacteria where they execute a wide array of discrete cellular functions. In this review, we have described the key structural deviations of bacterial Ig-folds when compared to the classical eukaryotic Ig-fold. Further, we have comprehensively grouped all the Ig domain containing adhesins present in both Gram-negative and Gram-positive bacteria. Additionally, we describe the role of these particular adhesins in host tissue attachment, colonization and subsequent infection by both pathogenic and non-pathogenic Escherichia coli as well as other bacterial species. The structural properties of these Ig-domain containing adhesins, along with their interactions with specific Ig-like and non Ig-like binding partners present on the host cell surface have been discussed in detail.

Considering B7-CD28 as a family through sequence and structure

With the emergence of immuno-oncology, new therapeutic agents that modulate immune activation and regulation are being used to treat cancer patients with durable response. It is well known that following T-cell receptor (TCR) activation, many co-receptors can augment or suppress the TCR signal, and therapeutically targeting these co-receptors has proven effective. The B7-CD28 family is comprised of such immune-regulatory receptors, and antibodies against its members programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized cancer treatment. These therapies promote an immune response against tumor cells, which demonstrated better long-term survival and tolerability compared to traditional cancer treatments. In this review we describe the history of the expanding B7-CD28 family, and by comparison of sequence and structure reveal that it is a non-traditional family. The family has grown to include proteins that share low sequence identity, generally grouped by regulation of immune response, which utilize the common immunoglobulin fold. This low level of commonality has provided additional challenges to the drug discovery process as the mechanisms and therapeutic potency between family members can vary greatly. Impact statement Immunotherapy as a field has dramatically expanded in the last decade in the area of oncology with efficacy demonstrated by PD-1, PD-L1, and CTLA-4 blockade. With all three “checkpoint blockade” receptors being in the B7-CD28 family, there has been increased interest in targeting other members in this family due to redundancy in immune regulation, i.e., the combination of therapeutic agents targeting multiple co-inhibitory receptors may yield additional antitumor efficacy. Therefore significant resources are being dedicated to developing additional B7-CD28 treatment options.

The Structure of the PapD-PapGII Pilin Complex Reveals an Open and Flexible P5 Pocket

ABSTRACTP pili are hairlike polymeric structures that mediate binding of uropathogenicEscherichia colito the surface of the kidney via the PapG adhesin at their tips. PapG is composed of two domains: a lectin domain at the tip of the pilus followed by a pilin domain that comprises the initial polymerizing subunit of the 1,000-plus-subunit heteropolymeric pilus fiber. Prior to assembly, periplasmic pilin domains bind to a chaperone, PapD. PapD mediates donor strand complementation, in which a beta strand of PapD temporarily completes the pilin domain's fold, preventing premature, nonproductive interactions with other pilin subunits and facilitating subunit folding. Chaperone-subunit complexes are delivered to the outer membrane usher where donor strand exchange (DSE) replaces PapD's donated beta strand with an amino-terminal extension on the next incoming pilin subunit. This occurs via a zip-in–zip-out mechanism that initiates at a relatively accessible hydrophobic space termed the P5 pocket on the terminally incorporated pilus subunit. Here, we solve the structure of PapD in complex with the pilin domain of isoform II of PapG (PapGIIp). Our data revealed that PapGIIp adopts an immunoglobulin fold with a missing seventh strand, complemented in parallel by the G1 PapD strand, typical of pilin subunits. Comparisons with other chaperone-pilin complexes indicated that the interactive surfaces are highly conserved. Interestingly, the PapGIIp P5 pocket was in an open conformation, which, as molecular dynamics simulations revealed, switches between an open and a closed conformation due to the flexibility of the surrounding loops. Our study reveals the structural details of the DSE mechanism.