Molecular crosstalk between adherens junction proteins, E-cadherin and nectin-4.

Cell-cell junctions formed by the association of cell adhesion molecules facilitate physiological events necessary for growth and development of multicellular organisms. Among them, cadherins and nectins organize and assemble to form adherens junction, which thereby mechanically couples interacting cells. A detailed understanding of the crosstalk involving these cell adhesion molecules is fundamental to the study of the various developmental processes. Although, cadherins and nectins can recruit each other in the adherens junction through an interplay of cytoplasmic adaptor molecules, here, we report a direct interaction between N-terminal extracellular domains of E-cadherin and nectin-4 as demonstrated by surface plasmon resonance (SPR) and Atomic Force Microscopy (AFM)-based single molecule force spectroscopy (SMFS). Kinetic studies using SPR demonstrate the binding between the ectodomains of E-cadherin and nectin-4 with a KD of 3.7 ± 0.7 µM and KD of 5.4 ± 0.2 µM (reciprocal experiment). AFM-based SMFS experiments also support interaction between the ectodomains of E-cadherin and nectin-4 with the koff value of 31.48 ± 1.53 s-1 and the lifetime of the complex of 0.036 ± 0.0026 s. We thus propose a cell adhesion mechanism mediated by E-cadherin and nectin-4, which can have functional significance in early embryogenesis as evident from the expression pattern of both the proteins during early development.

N-terminal ectodomain of BTNL2 inhibits T cell activation via a non-canonical interaction with its putative receptor that results in a delayed progression of DSS-induced ulcerative colitis.

Butyrophilin-like 2 (BTNL2) is a T cell inhibitory molecule that interacts with unknown binding partners to modulate the immune response in a number of inflammatory and autoimmune diseases. In this study, we found that the inhibitory effects of BTNL2 on T cell activation and effector functions can be executed by its N-terminal IgV domain (BTNL2 IgV1) alone. Structure-guided mutation of key residues on BTNL2 IgV1 based on known receptor-ligand interfaces involving immunoglobulin superfamily members revealed that BTNL2 uses a non-canonical binding interface with its putative receptor. A high avidity BTNL2 IgV1 probe revealed that in an inducible model of ulcerative colitis, severe colitis was accompanied by a selective enrichment of BTNL2-receptor expressing effector-memory CD4+ and CD8+ T cells in the Peyer's patches. Intraperitoneal administration of BTNL2 IgV1 resulted in a significant delay in the progression of DSS-induced colitis and also showed reduced activation of the BTNL2-receptor-expressing T cells in the Peyer's patches. Thus, this study demonstrates that the BTNL2-receptor-expressing T cells in the Peyer's patches participate in the disease pathogenesis and can serve as a novel therapeutic target in ulcerative colitis, which can be modulated by BTNL2 IgV1.

Structural basis of molecular recognition among classical cadherins mediating cell adhesion.

Cadherins are type-I membrane glycoproteins that primarily participate in calcium-dependent cell adhesion and homotypic cell sorting in various stages of embryonic development. Besides their crucial role in cellular and physiological processes, increasing studies highlight their involvement in pathophysiological functions ranging from cancer progression and metastasis to being entry receptors for pathogens. Cadherins mediate these cellular processes through homophilic, as well as heterophilic interactions (within and outside the superfamily) by their membrane distal ectodomains. This review provides an in-depth structural perspective of molecular recognition among type-I and type-II classical cadherins. Furthermore, this review offers structural insights into different dimeric assemblies like the 'strand-swap dimer' and 'X-dimer' as well as mechanisms relating these dimer forms like 'two-step adhesion' and 'encounter complex'. Alongside providing structural details, this review connects structural studies to bond mechanics merging crystallographic and single-molecule force spectroscopic findings. Finally, the review discusses the recent discoveries on dimeric intermediates that uncover prospects of further research beyond two-step adhesion.

Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry.

Viruses are obligate intracellular parasites that depend on host cellular machinery for performing even basic biological functions. One of the many ways they achieve this is through molecular mimicry, wherein the virus mimics a host sequence or structure, thereby being able to hijack the host's physiological interactions for its pathogenesis. Such adaptations are specific recognitions that often confer tissue and species-specific tropisms to the virus, and enable the virus to utilise previously existing host signalling networks, which ultimately aid in further steps of viral infection, such as entry, immune evasion and spread. A common form of sequence mimicry utilises short linear motifs (SLiMs). SLiMs are short-peptide sequences that mediate transient interactions and are major elements in host protein interaction networks. This work is aimed at providing a comprehensive review of current literature of some well-characterised SLiMs that play a role in the attachment and entry of viruses into host cells, which mimic physiological receptor-ligand interactions already present in the host. Considering recent trends in emerging diseases, further research on such motifs involved in viral entry can help in the discovery of previously unknown cellular receptors utilised by viruses, as well as help in the designing of targeted therapeutics such as vaccines or inhibitors directed towards these interactions.