Erasmus Syndrome: Silicosis and Systemic Sclerosis.

Several occupational hazards, especially exposure to silica, have been implicated as causal factors for the development of scleroderma-like disorders. Compared to other connective tissue disorders, silica-associated systemic sclerosis (SA-SS) is relatively rare. Silica-induced scleroderma is indistinguishable from idiopathic systemic sclerosis.

Structural Analysis of the Myo1c and Neph1 Complex Provides Insight into the Intracellular Movement of Neph1.

The Myo1c motor functions as a cargo transporter supporting various cellular events, including vesicular trafficking, cell migration, and stereociliary movements of hair cells. Although its partial crystal structures were recently described, the structural details of its interaction with cargo proteins remain unknown. This study presents the first structural demonstration of a cargo protein, Neph1, attached to Myo1c, providing novel insights into the role of Myo1c in intracellular movements of this critical slit diaphragm protein.

SAXS data based global shape analysis of trigger factor (TF) proteins from E. coli, V. cholerae, and P. frigidicola: resolving the debate on the nature of monomeric and dimeric forms.

Dimerization of bacterial chaperone trigger factor (TF) is an inherent protein concentration based property which available biophysical characterization and crystal structures have kept debatable. We acquired small-angle X-ray scattering (SAXS) intensity data from different TF homologues from Escherichia coli (ECTF), Vibrio cholerae (VCTF), and Psychrobacter frigidicola (PFTF) while varying each protein concentration. We found that ECTF and VCTF adopt a compact dimeric shape at higher concentrations which did not resemble the "back-to-back" conformation reported earlier for ECTF from crystallography (PDB ID: 1W26 ).

Bilobed shape of PadA reveals the connectivity from single to multi-domain bacterial plasminogen activators.

The bacterial plasminogen activator, PadA activates bovine, ovine and caprine plasminogen but remains inert toward human plasminogen. It shows high sequence homology with human plasminogen activator, staphylokinase (SAK) but generates active-site in bovine plasminogen non-proteolytically, similar to streptokinase (SK). To examine the structural requirements for the function of this unique cofactor, attempts were made to visualize solution structure of the PadA using small-angle X-ray scattering (SAXS) data and compare its shape profile with structural models based on crystal structures of staphylokinase and streptokinase domains.

Differential role of HAMP-like linkers in regulating the functionality of the group III histidine kinase DhNik1p.

Nik1 orthologs are sensor kinases that function upstream of the high osmolarity glycerol/p38 MAPK pathway in fungi. They contain a poly-HAMP module at their N terminus, which plays a pivotal role in osmosensing as well as fungal death upon exposure to fludioxonil. DhNik1p is a typical member of this class that contains five HAMP domains and four HAMP-like linkers.

Low pH overrides the need of calcium ions for the shape-function relationship of calmodulin: resolving prevailing debates.

Calmodulin (CaM) regulates numerous cellular functions by sensing Ca(2+) levels inside cells. Although its structure as a function of the Ca(2+)-bound state remains hotly debated, no report is available on how pH independently or in interaction with Ca(2+) ions regulates shape and function of CaM. From SAXS data analysis of CaM at different levels of Ca(2+)-ion concentration and buffer pH, we found that (1) CaM molecules possess a Gaussian-chain-like shape in solution even in the presence of Ca(2+) ion or at low pH, (2) the global shape of apo CaM is very similar to its NMR structure rather than the crystal structures, (3) about 16 Ca(2+) ions or more are required per CaM molecule in solution to achieve the four-Ca(2+)-bound crystal structure, (4) low pH alone can impart shape changes in CaM similar to Ca(2+) ions, and (5) at different [Ca(2+)]/[CaM] ratio or pH values, the predominant shape of CaM is essentially a weighted average of its apo and fully activated shape.

Slit diaphragm protein Neph1 and its signaling: a novel therapeutic target for protection of podocytes against glomerular injury.

Podocytes are specialized epithelial cells that are critical components of the glomerular filtration barrier, and their dysfunction leads to proteinuria and renal failure. Therefore, preserving podocyte function is therapeutically significant. In this study, we identified Neph1 signaling as a therapeutic target that upon inhibition prevented podocyte damage from a glomerular injury-inducing agent puromycin aminonucleoside (PAN).

Substitution of glutamate residue by lysine in the dimerization domain affects DNA binding ability of HapR by inducing structural deformity in the DNA binding domain.

HapR has been given the status of a high cell density master regulatory protein in Vibrio cholerae. Though many facts are known regarding its structural and functional aspects, much still can be learnt from natural variants of the wild type protein. This work aims at investigating the nature of functional inertness of a HapR natural variant harboring a substitution of a conserved glutamate residue at position 117 which participates in forming a salt bridge by lysine (HapRV2G-E(117)K).

Towards strain-independent anti-influenza peptides: a SAXS- and modeling-based study.

Using small angle X-ray scattering (SAXS) data, we reconstructed the scattering shape of the Hemagglutinin (HA) trimer protein from five different influenza strains. Comparison with the known crystal structures-based information aided in identifying volumes pertaining to the glycosylation in the HA trimers. By merging sequence information on HA proteins from pathogenic strains of influenza, we identified a novel druggable pocket composed of residues which remained conserved during evolution, lack propensity to be glycosylated, and play important role in maintaining interchain contacts in the pH-sensitive head group.

Global shapes of F-actin depolymerization-competent minimal gelsolins: insight into the role of g2-g3 linker in pH/Ca2+ insensitivity of the first half.

Because of its ability to rapidly depolymerize F-actin, plasma gelsolin has emerged as a therapeutic molecule in different disease conditions. High amounts of exogenous gelsolin are, however, required to treat animal models of different diseases. Knowing that the F-actin depolymerizing property of gelsolin resides in its N terminus, we made several truncated versions of plasma gelsolin.

A communication network within the cytoplasmic domain of toll-like receptors has remained conserved during evolution.

Toll/IL-1R (TIR) domain, that is, the cytoplasmic domain, in toll-like receptors (TLRs) from different species showed high sequence conservation in stretches spread across the surface as well as the core of the domain. To probe the structure-function significance of these residues, especially those coming from the core of TIR domains, we analyzed molecular dynamics trajectories of sequence similarity based models of human TIR domains. This study brought forth that N-terminal of the TIR domain simultaneously interacts with the flanking residues of the BB loop and central β-sheets.

APOL1 null alleles from a rural village in India do not correlate with glomerulosclerosis.

Background: Among African-Americans, genome wide association revealed a strong correlation between the G1 and G2 alleles of APOL1 (apolipoproteinL1, also called trypanolytic factor) and kidney diseases including focal and segmental glomerulosclerosis, HIV-associated nephropathy and hypertensive nephrosclerosis. In the prevailing hypothesis, heterozygous APOL1 G1 and G2 alleles increase resistance against Trypanosoma that cause African sleeping sickness, resulting in positive selection of these alleles, but when homozygous the G1 and G2 alleles predispose to glomerulosclerosis. While efforts are underway to screen patients for G1 and G2 alleles and to better understand "APOL1 glomerulopathy," no data prove that these APOL1 sequence variants cause glomerulosclerosis.

Solution structure analysis of cytoplasmic domain of podocyte protein Neph1 using small/wide angle x-ray scattering (SWAXS).

Neph1 is present in podocytes, where it plays a critical role in maintaining the filtration function of the glomerulus, in part through signaling events mediated by its cytoplasmic domain that are involved in actin cytoskeleton organization. To understand the function of this protein, a detailed knowledge of the structure of the Neph1 cytoplasmic domain (Neph1-CD) is required. In this study, the solution structure of this domain was determined by small/wide angle x-ray scattering (SWAXS).

First structural model of full-length human tissue-plasminogen activator: a SAXS data-based modeling study.

Human tissue-plasminogen activator (t-PA) is a multidomain glycoprotein which holds high biomedical value due to its therapeutic role in clot-specific fibrinolysis. Although atomic-resolution structures of individual domains except Kringle1 are available, no structural information is available on how these domains and glycosylation are oriented in space relative to each other in the full-length protein. SAXS intensity profile acquired from samples of t-PA was used to "steer" structures of individual domains and the homology model of the first kringle domain to generate a structural model of the protein part of t-PA.

SAXS data analysis and modeling of tetravalent neutralizing antibody CD4-IgG2 -/+ HIV-1 gp120 revealed that first two gp120 bind to the same Fab arm.

This communication describes SAXS data based global structures of tetravalent antibody CD4-IgG2 and its dimeric to pentameric complexes with gp120s. Comparison of models brought forth that while the two CD4s grafted on each arm remain tightly packed in the unliganded antibody, they enable binding of first two gp120s preferentially to the same Fab arm in an asymmetric manner. Retention of residues in the CD4-Fab linker earlier reasoned to enable bi-fold collapse of gp120-bound soluble CD4, and observed asymmetry of the (CD4-IgG2)/(gp120)(2) complex suggest that encoded flexibility in CD4-Fab linker is a critical structure-function factor for this broad spectrum neutralizing antibody.