Structural Diversity and Mutational Challenges of Toll-Like Receptor 4 Antagonists as Inflammatory Pathway Blocker.

Toll-like receptor 4 (TLR4) is an important mediator that activates bacterial inflammation through its signaling pathway. It binds lipopolysaccharide (LPS) in the presence of myeloid differentiation protein 2 (MD2) to dimerise the TLR4-MD2-LPS complex. The TLR4 mediated signaling pathway stimulates cytokine production in humans, initiating inflammatory responses.

Role of ATP-Small Heat Shock Protein Interaction in Human Diseases.

Adenosine triphosphate (ATP) is an important fuel of life for humans and species. Its potential role in modulating cellular functions and implications in systemic, pulmonary, and ocular diseases is well studied. Plasma ATP has been used as a diagnostic and prognostic biomarker owing to its close association with disease's progression.

Identification of tear-based protein and non-protein biomarkers: Its application in diagnosis of human diseases using biosensors.

Discovery of robust, selective and specific biomarkers are important for early diagnosis and monitor progression of human diseases. Eye being a common target for several human diseases, vision impediment and complications are often associated with systemic and ocular diseases. Tears are bodily fluids that are closest to eye and are rich in protein content and other metabolites.

Glycation-mediated protein crosslinking and stiffening in mouse lenses are inhibited by carboxitin in vitro.

Proteins in the eye lens have negligible turnover and therefore progressively accumulate chemical modifications during aging. Carbonyls and oxidative stresses, which are intricately linked to one another, predominantly drive such modifications. Oxidative stress leads to the loss of glutathione (GSH) and ascorbate degradation; this in turn leads to the formation of highly reactive dicarbonyl compounds that react with proteins to form advanced glycation end products (AGEs).

Transient elevation of temperature promotes cross-linking of α-crystallin-client proteins through formation of advanced glycation endproducts: A potential role in presbyopia and cataracts.

The chaperone activity of α-crystallin is important for maintaining the transparency of the human lens. αB-crystallin (αBC) is a long-lived protein in the lens that accumulates chemical modifications during aging. The formation of advanced glycation end products (AGEs) through glycation is one such modification.

Glycation-mediated inter-protein cross-linking is promoted by chaperone-client complexes of α-crystallin: Implications for lens aging and presbyopia.

Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein-cross-linking AGEs.

M. leprae HSP18 suppresses copper (II) mediated ROS generation: Effect of redox stress on its structure and function.

Mycobacterium leprae, causative organism of leprosy, is known to counter redox stress generated by reactive oxygen species (ROS) during its survival inside host macrophages. But, the involvement of any antigenic protein(s) for countering such redox stress is still unknown. Interestingly, M.

The impact of different mutations at arginine141 on the structure, subunit exchange dynamics and chaperone activity of Hsp16.3.

Hsp16.3, a molecular chaperone, plays a vital role in the growth and survival of Mycobacterium tuberculosis inside the host. We previously reported that deletion of three amino acid residues ( STN ) from C-terminal extension (CTE) of Hsp16.

Lysine malonylation and propionylation are prevalent in human lens proteins.

Acylated lysine residues represent major chemical modifications in proteins. We investigated the malonylation and propionylation of lysine residues (MalK, PropK) in the proteins of aging human lenses. Western blot results showed that the two modifications are present in human lens proteins.

Systemically administered peptain-1 inhibits retinal ganglion cell death in animal models: implications for neuroprotection in glaucoma.

Axonal degeneration and death of retinal ganglion cells (RGCs) are the primary causes of vision loss in glaucoma. In this study, we evaluated the efficacy of a peptide (peptain-1) that exhibits robust chaperone and anti-apoptotic activities against RGC loss in two rodent models and in cultured RGCs. In cultures of rat primary RGCs and in rat retinal explants peptain-1 significantly decreased hypoxia-induced RGC loss when compared to a scrambled peptide.

The absence of SIRT3 and SIRT5 promotes the acetylation of lens proteins and improves the chaperone activity of α-crystallin in mouse lenses.

Acetylation of lysine residues occurs in lens proteins. Previous studies have shown an improvement in the chaperone activity of αA-crystallin upon acetylation. Sirtuins are NAD-dependent enzymes that can deacylate proteins.

Succinylation Is a Gain-of-Function Modification in Human Lens αB-Crystallin.

Acylation of lysine residues is a common post-translational modification of cellular proteins. Here, we show that lysine succinylation, a type of acylation, occurs in human lens proteins. All of the major crystallins exhibited N-succinyllysine (SuccK) residues.

A monoclonal antibody targeted to the functional peptide of αB-crystallin inhibits the chaperone and anti-apoptotic activities.

αB-Crystallin is a member of the small heat shock protein family. It is a molecular chaperone and an anti-apoptotic protein. Previous studies have shown that the peptide (DRFSVNLDVKHFSPEELKVKV, hereafter referred to as peptain-1) from the core domain of αB-crystallin exhibits both chaperone and anti-apoptotic properties similar to the parent protein.

Evidences for zinc (II) and copper (II) ion interactions with Mycobacterium leprae HSP18: Effect on its structure and chaperone function.

Mycobacterium leprae uptakes various bivalent metal ions via different transporters in host species. Uptake of Cu and Zn are essential for generation of superoxide dismutases and catalases, which provide defense against reactive oxygen species mediated death of this pathogen in macrophages. Furthermore, it has also been noticed that levels of different bivalent metal ions (Ca, Mg, Cu and Zn) in blood serum are altered in leprotic patients.

Probing the structure-function relationship of Mycobacterium leprae HSP18 under different UV radiations.

Ultraviolet radiation, an effective sterilizing source, rapidly kills the causative organism (Mycobacterium leprae) of leprosy. But, the reasons behind this quick death are not clearly understood. Also, the impact of UV radiation on the antigen(s) which is/are responsible for the survival of this pathogen is still unknown.

The C-terminal extension of Mycobacterium tuberculosis Hsp16.3 regulates its oligomerization, subunit exchange dynamics and chaperone function.

Mycobacterium tuberculosis is a human pathogen that secretes a major immunodominant antigen, namely Hsp16.3, throughout the course of infection. Hsp16.

Role of Subunit Exchange and Electrostatic Interactions on the Chaperone Activity of Mycobacterium leprae HSP18.

Mycobacterium leprae HSP18, a major immunodominant antigen of M. leprae pathogen, is a small heat shock protein. Previously, we reported that HSP18 is a molecular chaperone that prevents aggregation of different chemically and thermally stressed client proteins and assists refolding of denatured enzyme at normal temperature.

Differential role of arginine mutations on the structure and functions of α-crystallin.

Background: α-Crystallin is a major protein of the eye lens in vertebrates. It is composed of two subunits, αA- and αB-crystallin. α-Crystallin is an oligomeric protein having these two subunits in 3:1 ratio.

Interaction of ATP with a small heat shock protein from Mycobacterium leprae: effect on its structure and function.

Adenosine-5'-triphosphate (ATP) is an important phosphate metabolite abundantly found in Mycobacterium leprae bacilli. This pathogen does not derive ATP from its host but has its own mechanism for the generation of ATP. Interestingly, this molecule as well as several antigenic proteins act as bio-markers for the detection of leprosy.

Acetylation of Gly1 and Lys2 promotes aggregation of human γD-crystallin.

The human lens contains three major protein families: α-, β-, and γ-crystallin. Among the several variants of γ-crystallin in the human lens, γD-crystallin is a major form. γD-Crystallin is primarily present in the nuclear region of the lens and contains a single lysine residue at the second position (K2).

Acetylation of lysine 92 improves the chaperone and anti-apoptotic activities of human αB-crystallin.

αB-Crystallin is a chaperone and an anti-apoptotic protein that is strongly expressed in many tissues, including the lens, retina, heart, and kidney. In the human lens, several lysine residues in αB-crystallin are acetylated. We have previously shown that such acetylation is predominant at lysine 92 (K92) and lysine 166 (K166).

A S52P mutation in the 'α-crystallin domain' of Mycobacterium leprae HSP18 reduces its oligomeric size and chaperone function.

Mycobacterium leprae HSP18 is a small heat shock protein (sHSP). It is a major immunodominant antigen of M. leprae pathogen.