Globular Proteins Research Articles

A General and Convenient Peptide Self-Assembling Mechanism for Developing Supramolecular Versatile Nanomaterials Based on The Biosynthetic Hybrid Amyloid-Resilin Protein.

Self-assembling peptides are valuable building blocks to fabricate supramolecular biomaterials, which have broad applications from biomedicine to biotechnology. However, limited choices to induce different globular proteins into hydrogels hinder these designs. Here, an easy-to-implement and tunable self-assembling strategy, which employs Ure2 amyloidogenic peptide, are described to induce any target proteins to assemble into supramolecular hydrogels alone or in combination with notable compositional control. Furthermore, the collective effect of nanoscale interactions among amyloid nanofibrils and partially disordered elastomeric polypeptides are investigated. This led to many useful macroscopic material properties simultaneously emerging from one pure protein material, i.e. strong adhesion to any substrates under wet conditions, rapidly self--assembling into robust and porous hydrogels, adaptation to remodeling processes, strongly promoting cell adhesion, proliferation and differentiation. Moreover, he demonstrated this supramolecular material's robust performance in vitro and vivo for tissue engineering, cosmetic and hemostasis applications and exhibited superior performance compared to corresponding commercial counterparts. To the best of his knowledge, few pure protein-based materials could meet such seemingly mutually exclusive properties simultaneously. Such versatility renders this novel supramolecular nanomaterial as next-generation functional protein-based materials, and he demonstrated the sequence level modulation of structural order and disorder as an untapped principle to design new proteins.

Protein intrinsically disordered regions have a non-random, modular architecture.

Protein sequences can be broadly categorized into two classes: those which adopt stable secondary structure and fold into a domain (i.e. globular proteins), and those that do not. The sequences belonging to this latter class are conformationally heterogeneous and are described as being intrinsically disordered. Decades of investigation into the structure and function of globular proteins has resulted in a suite of computational tools that enable their sub-classification by domain type, an approach that has revolutionized how we understand and predict protein functionality. Conversely, it is unknown if sequences of disordered protein regions are subject to broadly generalizable organizational principles that would enable their sub-classification. Here, we report the development of a statistical approach that quantifies linear variance in amino acid composition across a sequence. With multiple examples, we provide evidence that intrinsically disordered regions are organized into statistically non-random modules of unique compositional bias. Modularity is observed for both low and high-complexity sequences and, in some cases, we find that modules are organized in repetitive patterns. These data demonstrate that disordered sequences are non-randomly organized into modular architectures and motivate future experiments to comprehensively classify module types and to determine the degree to which modules constitute functionally separable units analogous to the domains of globular proteins. The source code, documentation, and data to reproduce all figures are freely available at https://github.com/MWPlabUTSW/Chi-Score-Analysis.git. The analysis is also available as a Google Colab Notebook (https://colab.research.google.com/github/MWPlabUTSW/Chi-Score-Analysis/blob/main/ChiScore_Analysis.ipynb).

Effective interactions and phase behavior of protein solutions in the presence of hexamine cobalt(III) chloride

It is well established that deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) exhibit a reentrant condensation (RC) phase behavior in the presence of the trivalent hexamine cobalt(III) cations (Hac) which can be important for their packing and folding. A similar behavior can be observed for negatively charged globular proteins in the presence of trivalent metal cations, such as Y3+ or La3+. This phase behavior is mainly driven by charge inversion upon an increasing salt concentration for a fixed protein concentration (cp). However, as Hac exhibits structural differences compared to other multivalent metal cations, with six ammonia ligands (NH3) covalently bonded to the central cobalt atom, it is not clear that Hac can induce a similar phase behavior for proteins. In this work, we systematically investigate whether negatively charged globular proteins β-lactoglobulin (BLG), bovine serum albumin (BSA), human serum albumin (HSA) and ovalbumin (OVA) feature Hac-induced RC. Effective protein–protein interactions were investigated by small-angle X-ray scattering. The reduced second virial coefficient (B2/B2HS) was obtained as a function of salt concentration. The virial coefficient analysis performed confirms the reentrant interaction (RI) behavior for BLG without actually inducing RC, given the insufficient strengths of the interactions for the latter to occur. In contrast, the strength of attraction for BSA, HSA and OVA are too weak to show RC. Model free analysis of the inverse intensity 1/Iq→0\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$1/I\\left( {q \ o 0} \\right)$$\\end{document} also supports this finding. Looking at different q-range by employing static (SLS) and dynamic light scattering experiments, the presence of RI behavior can be confirmed. The results are further discussed in view of metal cation binding sites in nucleic acids (DNA and RNA), where Hac induced RC phase behavior.Graphical abstract

Results from the Completed Dose Escalation Portion of the Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (MM)

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM). Methods This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria. Results Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts. All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses. Conclusions Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Dry sliding wear behavior of AA7075 alloy produced by thixocasting

Abstract In this study, the wear behavior of AA7075 alloy produced by thixocasting was investigated. The wear behavior of the AA7075 alloy is examined for three cases: extruded with T6 heat treatment, as-thixocast, and thixocast with T6 conditions. The dry sliding wear test was conducted with a tribometer according to ASTM G-99 standard. The microstructures were characterized by optical microscopy, scanning electron microscopy (SEM), and energy-dispersive X-ray analysis (EDX). The tensile and hardness tests were performed to evaluate the mechanical properties. The AA7075 alloy was successfully shaped by thixocasting. The as-thixocast sample exhibited typical globular structures with multinary eutectic structures along the grain boundaries. The globular grains transform into a polygonal structure, and the grain size increases from 50 μm to 60 μm in the thixocast + T6 sample. This microstructure exhibited excellent wear resistance under dry sliding conditions in the thixocast + T6 sample. The aging treatment with prolonged solution process improved the mechanical properties two times and the wear rate three times for the thixocast AA7075 alloy. Furthermore, the thixocast + T6 sample exhibited a significant decrease in the coefficient of friction with the lowest wear rate compared to the as-thixocast sample. The dominant wear mechanisms are microdelamination, adhesion, and oxidation in all samples.

Basic protein- and peptide-induced stabilization of long-loop DNA G-guadruplexes

The human genome contains many G-quadruplex-forming sequences, including sequences containing long single-stranded loops that are believed to be unfavorable for G-quadruplex formation. The intracellular environment of biological cells is crowded with proteins with charged surfaces. Understanding the effects of protein-rich environments is important for understanding the formation of G-quadruplexes in an intracellular environment. In this study, we investigated the structural stability of DNA G-quadruplexes in the presence of several types of globular proteins (lysozyme, cytochrome c, bovine serum albumin, myoglobin, histone proteins, and serum proteins), unstructured polypeptides (protamine and poly-l-lysine), and oligopeptides (RGG/RG-domain peptides and short repeated peptides). Thermal melting studies of G-quadruplex-forming oligonucleotides derived from the human telomeric repeat sequence revealed that environments containing high concentrations of proteins and peptides differently affected the G-quadruplex stability according to their loop lengths. We found that weak electrostatic interactions of G-quadruplex loops with basic proteins and peptides improved the stability of long-loop G-quadruplexes and the interactions were strengthened under crowded conditions simulated by dextran. The comparison of the effects of different types of proteins and peptides indicated that excluded volume interactions and structural flexibility of both DNA and polypeptide chains influenced the efficiency of their interactions. This study provides insights into long-loop G-quadruplex stability in a crowded intracellular environment and the recognition of G-quadruplexes by arginine-rich domains of G-quadruplex-binding proteins.

Influence of Various Alloying Element Additions on Microstructure and Magnetic and Mechanical Properties and Corrosion Behavior of Cast Fe–Ga–Z Shape Memory Alloys

Fe–Ga alloys are attractive materials where high mechanical strength, toughness, ductility, and large low-field magnetostriction combine to give unique properties. Adding alloying elements is an effective method to further enhance these properties. In order to integrate these alloys into the operating environments, e.g., micro-robots and magnetic actuators, the corrosion behavior should be addressed. This work analyzed the microstructure, magnetization, hardness, and corrosion properties of Fe81Ga19−xZx (X = 5 at.% of Ni, Mn, or Ti, and 2 at.% Al; separately) alloys. X-ray diffraction (XRD), scanning electron microscope-electron (SEM), vibrating sample magnetometer (VSM), Vickers hardness (HV), and a potentiostat were used for characterization. XRD revealed that the prominent peak belongs to the bcc disorder A2 phase and a small peak for the cubic order L12 phase. Fe–Ga–Al alloy got the maximum Ms value, while Fe–Ga–Mn alloy gained the lowest one. However, the Mr and Hc properties for Fe–Ga alloy were distinctly improved by adding Al but slightly affected by doping Mn. Addition of Ti achieved the highest hardness, followed by Ni, Mn, and Al. The microstructure of the different alloys significantly influenced their corrosion behavior. Fe–Ga–Mn alloy with the fine globular grain structure showed the lowest corrosion rate (C R = 0.03 mm/year), whereas Fe–Ga–Al alloy with the coarse longitudinal grains exhibited the highest corrosion rate (C R = 0.19 mm/year).

Phase partitioning nature, interaction forces and thermodynamic parameters of triton X-100 and bovine serum albumin mixture: impacts of the composition of Na-salt

Herein, the assessment of interactions between a non-ionic surfactant (NIS) triton X-100 (TNX-100) and a globular protein bovine serum albumin (BSA) was explored through the determination of clouding nature in aqueous solution of sodium salts (Na-salts). Sodium chloride (NaCl), sodium acetate (NaOAc), sodium carbonate (Na2CO3), sodium oxalate (Na2Oxal), sodium sulphate (Na2SO4), and sodium phosphate (Na3PO4) have been chosen to assess their impacts on the clouding nature of TNX-100 + BSA mixture. The estimated cloud point (CP) values were noticed to be lowered with the enhancement of [Na-salts]. The lessening of CP values has been explained by the salting out effect of anions. The calculated standard Gibbs free energy change () was positive at all examined conditions which illustrates the nonspontaneity of phase change. The standard enthalpy () and entropy () changes exhibited negative values at low contents of aq. Na-salts and positive values at high aq. Na-salts content. These consequences illustrate the presence of electrostatic interactions at low Na-salts concentration and hydrophobic interactions at high Na-salts concentration. Furthermore, enthalpy-entropy parameters were successfully computed and explained with proper clarification.

Cationic Materials for Gene Therapy: A Look Back to the Birth and Development of 2,2-Bis-(hydroxymethyl)Propanoic Acid-Based Dendrimer Scaffolds.

Gene therapy is extensively studied as a realistic and promising therapeutic approach for treating inherited and acquired diseases by repairing defective genes through introducing (transfection) the "healthy" genetic material in the diseased cells. To succeed, the proper DNA or RNA fragments need efficient vectors, and viruses are endowed with excellent transfection efficiency and have been extensively exploited. Due to several drawbacks related to their use, nonviral cationic materials, including lipidic, polymeric, and dendrimer vectors capable of electrostatically interacting with anionic phosphate groups of genetic material, represent appealing alternative options to viral carriers. Particularly, dendrimers are highly branched, nanosized synthetic polymers characterized by a globular structure, low polydispersity index, presence of internal cavities, and a large number of peripheral functional groups exploitable to bind cationic moieties. Dendrimers are successful in several biomedical applications and are currently extensively studied for nonviral gene delivery. Among dendrimers, those derived by 2,2-bis(hydroxymethyl)propanoic acid (b-HMPA), having, unlike PAMAMs, a neutral polyester-based scaffold, could be particularly good-looking due to their degradability in vivo. Here, an overview of gene therapy, its objectives and challenges, and the main cationic materials studied for transporting and delivering genetic materials have been reported. Subsequently, due to their high potential for application in vivo, we have focused on the biodegradable dendrimer scaffolds, telling the history of the birth and development of b-HMPA-derived dendrimers. Finally, thanks to a personal experience in the synthesis of b-HMPA-based dendrimers, our contribution to this field has been described. In particular, we have enriched this work by reporting about the b-HMPA-based derivatives peripherally functionalized with amino acids prepared by us in recent years, thus rendering this paper original and different from the existing reviews.

Natural and Engineered Isoforms of the Inflammasome Adaptor ASC Form Noncovalent, pH-Responsive Hydrogels.

The protein ASC polymerizes into intricate filament networks to assemble the inflammasome, a filamentous multiprotein complex that triggers the inflammatory response. ASC carries two Death Domains integrally involved in protein self-association for filament assembly. We have leveraged this behavior to create noncovalent, pH-responsive hydrogels of full-length, folded ASC by carefully controlling the pH as a critical factor in the polymerization process. We show that natural variants of ASC (ASC isoforms) involved in inflammasome regulation also undergo hydrogelation. To further demonstrate this general capability, we engineered proteins inspired by the ASC structure that also form hydrogels. We analyzed the structural network of the natural and engineered protein hydrogels using transmission and scanning electron microscopy and studied their viscoelastic behavior using shear rheology. Our results reveal one of the very few examples of hydrogels created by the self-assembly of globular proteins and domains in their native conformation and show that Death Domains can be used alone or as building blocks to engineer bioinspired hydrogels.

Conservation of knotted and slipknotted topology in transmembrane transporters

The existence of nontrivial topology is well accepted in globular proteins but not in membrane proteins. Our comprehensive topological analysis of the Protein Data Bank structures reveals 18 families of transmembrane proteins with nontrivial topology, showing that they constitute a significant number of membrane proteins. Moreover, we found that they comprise one of the largest groups of secondary active transporters. We classified them based on their knotted fingerprint into four groups: three slipknotted and one knotted. Unexpectedly, we found that the same protein can possess two distinct slipknot motifs that correspond to its outward- and inward-open conformational state. Based on the analysis of structures and knotted fingerprints, we show that slipknot topology is directly involved in the conformational transition and substrate transfer. Therefore, entanglement can be used to classify proteins and to find their structure-function relationship. Furthermore, based on the topological analysis of the transmembrane protein structures predicted by AlphaFold, we identified new potentially slipknotted protein families.

PLDDT Values in AlphaFold2 Protein Models Are Unrelated to Globular Protein Local Flexibility

Two non-redundant, high-quality sets of protein X-ray crystal structures from the Protein Data Bank (room temperature, 288–298 K, and low temperature, 95–105 K) were compared to structural predictions conducted using ColabFold/AlphaFold2. In particular, the relationship between B-factors and pLDDT values, which estimate the degree of prediction confidence, was investigated. It was observed that there is basically no correlation between these two quantities and, consequently, that the level of confidence in predictions does not provide information about the degree of local structural flexibility of globular proteins.

Influence of amyloid fibril length and ionic strength on WPI-based fiber-hydrogel composites: Microstructural, rheological and water holding properties

One of the possible advantages of protein fibers in composites is that they can interact with the continuous gel matrix as active fillers at neutral pH. This study aimed to investigate the impacts of short (SAF) and long amyloid fibrils (LAF) and ionic strength (0–150 mM NaCl) on the whey protein isolate (WPI)-based fiber-hydrogel composites. The water holding capacity of the composite gels more depended on the gel coarseness rather than their elasticity. Significant differences were observed between the rheological data of the SAF-WPI and LAF-WPI composites, and the maximum elastic modulus (G′) was achieved at 100 mM NaCl where the LAF-WPI composites outperformed the SAF-WPI ones in enhancing G′ and hardness. Nevertheless, the elasticity and hardness of the composites dramatically dropped at 150 mM NaCl due to the change in the gel microstructure from fine strand to particulate, according to CLSM and SEM images. Interestingly, the trend in average particle size changed at 150 mM NaCl for the SAF- and LAF-WPI soluble aggregates compared to the WPI soluble aggregates. The effects of amyloid fibril and NaCl concentration on the protein aggregates as the initial building blocks of the gel were confirmed by size exclusion chromatography. These results indicated that the properties of composite gel were related to the balance between aggregate creation and the development of cross-links between them during gelation. The findings of the current study could be exploited to predict the functional behavior of globular protein gels containing amyloid fibrils with different lengths at various NaCl concentrations.

Lysozyme stability in various deep eutectic solvents using molecular dynamics simulations

The ability of neat deep eutectic solvents (DESs) to influence protein structure and function has gained considerable interest due to the unstable nature of enzymes or therapeutic proteins, which are often exposed to thermal, chemical, or mechanical stresses when handled at an industrial scale. In this study, we simulated a model globular protein, lysozyme, in water and six choline chloride-based DES using molecular dynamics simulations, to investigate the structural changes in various solvent environments, giving insights into the overall stability of lysozyme. Root mean square deviation (RMSD) and root mean square fluctuations (RMSF) of the C-α backbone indicated that most DESs induced a less flexible and rigid lysozyme structure compared to water. The radius of gyration and end-to-end distance calculations pointed towards higher structural compactness in reline and levuline, while the structure of lysozyme considerably expanded in oxaline. Protein-solvent interactions were further analysed by hydrogen bonding interactions and radial distribution functions (RDF), which indicated a higher degree of lysozyme-hydrogen bond donor (HBD) interactions compared to lysozyme-choline hydrogen bonding. Surface area analysis revealed an overall % increase in total positive, negative, donor, and acceptor surface areas in malicine and oxaline compared to water and other DESs, indicating the exposure of a larger number of residues to interactions with the solvent. Reline, levuline, and polyol-based DESs comparatively stabilized lysozyme, even though changes in the secondary/tertiary structures were observed. Communicated by Ramaswamy H. Sarma

An amino-domino model described by a cross-peptide-bond Ramachandran plot defines amino acid pairs as local structural units.

Protein structure, both at the global and local level, dictates function. Proteins fold from chains of amino acids, forming secondary structures, α-helices and β-strands, that, at least for globular proteins, subsequently fold into a three-dimensional structure. Here, we show that a Ramachandran-type plot focusing on the two dihedral angles separated by the peptide bond, and entirely contained within an amino acid pair, defines a local structural unit. We further demonstrate the usefulness of this cross-peptide-bond Ramachandran plot by showing that it captures β-turn conformations in coil regions, that traditional Ramachandran plot outliers fall into occupied regions of our plot, and that thermophilic proteins prefer specific amino acid pair conformations. Further, we demonstrate experimentally that the effect of a point mutation on backbone conformation and protein stability depends on the amino acid pair context, i.e., the identity of the adjacent amino acid, in a manner predictable by our method.

Dynamic Properties of Adsorption Layers of κ-Casein Fibrils.

The dynamic surface properties of native κ-casein solutions and aqueous dispersions of its fibrils differ significantly from the corresponding properties of the systems with globular proteins. The dependence of the dynamic surface elasticity of κ-casein solutions on surface pressure has a local maximum, indicating partial displacement of macromolecules from the proximal region of the surface layer to the distal one. This dependence becomes monotonic for fibril dispersions, similar to the results for dispersions of globular protein fibrils, but unlike the latter case, the surface elasticity close to the steady state reaches values that are approximately four times higher than the data for native protein solutions at the same concentrations.

The Functionality of IbpA from Acholeplasma laidlawii Is Governed by Dynamic Rearrangement of Its Globular-Fibrillar Quaternary Structure.

Small heat shock proteins (sHSPs) represent a first line of stress defense in many bacteria. The primary function of these molecular chaperones involves preventing irreversible protein denaturation and aggregation. In Escherichia coli, fibrillar EcIbpA binds unfolded proteins and keeps them in a folding-competent state. Further, its structural homologue EcIbpB induces the transition of EcIbpA to globules, thereby facilitating the substrate transfer to the HSP70-HSP100 system for refolding. The phytopathogenic Acholeplasma laidlawii possesses only a single sHSP, AlIbpA. Here, we demonstrate non-trivial features of the function and regulation of the chaperone-like activity of AlIbpA according to its interaction with other components of the mycoplasma multi-chaperone network. Our results show that the efficiency of the A. laidlawii multi-chaperone system is driven with the ability of AlIbpA to form both globular and fibrillar structures, thus combining functions of both IbpA and IbpB when transferring the substrate proteins to the HSP70-HSP100 system. In contrast to EcIbpA and EcIbpB, AlIbpA appears as an sHSP, in which the competition between the N- and C-terminal domains regulates the shift of the protein quaternary structure between a fibrillar and globular form, thus representing a molecular mechanism of its functional regulation. While the C-terminus of AlIbpA is responsible for fibrils formation and substrate capture, the N-terminus seems to have a similar function to EcIbpB through facilitating further substrate protein disaggregation using HSP70. Moreover, our results indicate that prior to the final disaggregation process, AlIbpA can directly transfer the substrate to HSP100, thereby representing an alternative mechanism in the HSP interaction network.

Oligomeric and Fibrillar α-Synuclein Display Persistent Dynamics and Compressibility under Controlled Confinement.

The roles of α-synuclein in neurotransmitter release in brain neurons and in the Parkinson's disease condition have challenged comprehensive description. To gain insight into molecular mechanistic properties that actuate α-synuclein function and dysfunction, the coupled protein and solvent dynamics of oligomer and fibril forms of human α-synuclein are examined in a low-temperature system that allows control of confinement and localization of a motionally sensitive electron paramagnetic resonance spin probe in the coupled solvent-protein regions. The rotational mobility of the spin probe resolves two distinct α-synuclein-associated solvent components for oligomers and fibrils, as for globular proteins, but with dramatically higher fluidities at each temperature, that are comparable to low-confinement, aqueous-cryosolvent mesophases. In contrast to the temperature-independent volumes of the solvent phases that surround globular and condensate-forming proteins, the higher-fluidity mesophase volume of α-synuclein oligomers and fibrils decreases with decreasing temperature, signaling a compression of this phase. This unique property and thermal hysteresis in the mobilities and component weights, together with previous high-resolution structural characterizations, suggest a model in which the dynamically disordered C-terminal domain of α-synuclein creates a compressible phase that maintains high fluidity under confinement. Robust dynamics and compressibility are fundamental molecular mechanical properties of α-synuclein oligomers and fibrils, which may contribute to dysfunction and inform about function.

Dermoscopic Diagnosis of a Non-Pigmented Skin Tumor: Eccrine Poroma

Dear Editor, Eccrine poroma stands as a benign adnexal neoplasm that originates from the acrosyringium. It typically emerges as solitary, flesh-colored, or erythematous papules, plaques, or nodules, primarily appearing in areas with sweat glands. As well as pigmented lesions, dermoscopy has proven to enhance the clinical diagnosis of numerous non-pigmented skin tumors, including eccrine poroma. Herein we present a case of eccrine poroma located on the dorsal aspect of the left foot, with characteristic dermoscopic features. A 60-year-old woman was admitted with an asymptomatic lesion on the dorsum of her left foot, which had manifested approximately four years before. Clinically, the lesion presented as a well-circumscribed, violaceous, 0.9x0.9 cm papule (Figure 1a). Dermoscopic examination revealed flower-like and leaf-like vascular patterns, white interlacing areas, glomerular vessels, and milky red globules (Figures 1c-d). The lesion was excised and histopathologic findings were consistent with eccrine poroma (Figure 1b). Eccrine poroma (EP) is an adnexal tumor originating in the intraepidermal part of the eccrine sweat gland duct. Dermoscopy and histopathology help to differentiate EP from pyogenic granuloma, seborrheic keratosis, verruca vulgaris, basal cell carcinoma, squamous cell carcinoma, and amelanotic melanoma. Well-defined dermoscopic features in EP are: White interlacing areas around vessels, milky-red globules, flower-like and leaf-like vascular patterns, glomerular vessels, hairpin vessels, yellow structureless areas, poorly visualized vessels, and well-circumscribed globular or lacuna-like structures separated by white to pink mesh bands [1-3]. Histologically, EP manifests as a well-contained tumor constituted of proliferative cuboidal or poroid cells, often extending from the basal epidermis into the dermal layer. Shave, electrosurgical destruction or simple excision may be the treatment of lesions, depending on the depth of the lesion. Kind Regards

Water molecule ordering on the surface of an intrinsically disordered protein

The dynamics and local structure of the hydration water on surfaces of folded proteins have been extensively investigated. However, our knowledge of the hydration of intrinsically disordered proteins (IDPs) is more limited. Here, we compare the local structure of water molecules hydrating a globular protein, lysozyme, and the intrinsically disordered N-terminal of c-Src kinase (SH4UD) using molecular dynamics simulation. The radial distributions from the protein surface of the first and the second hydration shells are similar for the folded protein and the IDP. However, water molecules in the first hydration shell of both the folded protein and the IDP are perturbed from the bulk. This perturbation involves a loss of tetrahedrality, which is, however, significantly more marked for the folded protein than the IDP. This difference arises from an increase in the first hydration shell of the IDP of the fraction of hydration water molecules interacting with oxygen. The water ordering is independent of the compactness of the IDP. In contrast, the lifetimes of water molecules in the first hydration shell increase with IDP compactness, indicating a significant impact of IDP configuration on water surface pocket kinetics, which here is linked to differential pocket volumes and polarities.