Different PSMA Radiopharmaceuticals: A Comparative Study of [F]F-PSMA-1007, [F]F-JK-PSMA-7, and [Tc]Tc-PSMA-I&S in the Skeletal System.

Background: Numerous PSMA-based tracers are used for diagnostic prostate cancer imaging, but comprehensive comparisons between multiple ligands are lacking. This study aimed to compare physiological skeletal uptake and tracer uptake in commonly recommended PSMA reference regions across three different PSMA ligands in prostate cancer patients.

Methods: A total of 281 prostate cancer patients were included.

Unveiling the Complexity of cis-Regulation Mechanisms in Kinases: A Comprehensive Analysis.

Protein cis-regulatory elements (CREs) are regions that modulate the activity of a protein through intramolecular interactions. Kinases, pivotal enzymes in numerous biological processes, often undergo regulatory control via inhibitory interactions in cis. This study delves into the mechanisms of cis regulation in kinases mediated by CREs, employing a combined structural and sequence analysis.

Recurrent evolution of adhesive defence systems in amphibians by parallel shifts in gene expression.

Natural selection can drive organisms to strikingly similar adaptive solutions, but the underlying molecular mechanisms often remain unknown. Several amphibians have independently evolved highly adhesive skin secretions (glues) that support a highly effective antipredator defence mechanism. Here we demonstrate that the glue of the Madagascan tomato frog, Dyscophus guineti, relies on two interacting proteins: a highly derived member of a widespread glycoprotein family and a galectin.

Condensation of the N-terminal domain of human topoisomerase 1 is driven by electrostatic interactions and tuned by its charge distribution.

Liquid-liquid phase separation (LLPS) is pivotal in forming biomolecular condensates, which are crucial in several biological processes. Intrinsically disordered regions (IDRs) are typically responsible for driving LLPS due to their multivalency and high content of charged residues that enable the establishment of electrostatic interactions. In our study, we examined the role of charge distribution in the condensation of the disordered N-terminal domain of human topoisomerase I (hNTD).

A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription.

The essential G-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1.

Biophysical characterization of the Plasmodium falciparum circumsporozoite protein's N-terminal domain.

The circumsporozoite protein (CSP) is the main surface antigen of the Plasmodium sporozoite (SPZ) and forms the basis of the currently only licensed anti-malarial vaccine (RTS,S/AS01). CSP uniformly coats the SPZ and plays a pivotal role in its immunobiology, in both the insect and the vertebrate hosts. Although CSP's N-terminal domain (CSP ) has been reported to play an important role in multiple CSP functions, a thorough biophysical and structural characterization of CSP is currently lacking.

PED in 2024: improving the community deposition of structural ensembles for intrinsically disordered proteins.

The Protein Ensemble Database (PED) (URL: https://proteinensemble.org) is the primary resource for depositing structural ensembles of intrinsically disordered proteins. This updated version of PED reflects advancements in the field, denoting a continual expansion with a total of 461 entries and 538 ensembles, including those generated without explicit experimental data through novel machine learning (ML) techniques.

Minimum information guidelines for experiments structurally characterizing intrinsically disordered protein regions.

An unambiguous description of an experiment, and the subsequent biological observation, is vital for accurate data interpretation. Minimum information guidelines define the fundamental complement of data that can support an unambiguous conclusion based on experimental observations. We present the Minimum Information About Disorder Experiments (MIADE) guidelines to define the parameters required for the wider scientific community to understand the findings of an experiment studying the structural properties of intrinsically disordered regions (IDRs).

Quantification of Surface Tension Effects and Nucleation-and-Growth Rates during Self-Assembly of Biological Condensates.

Liquid-solid and liquid-liquid phase separation (PS) drives the formation of functional and disease-associated biological assemblies. Principles of phase equilibrium are here employed to derive a general kinetic solution that predicts the evolution of the mass and size of biological assemblies. Thermodynamically, protein PS is determined by two measurable concentration limits: the saturation concentration and the critical solubility.

The evolution and polymorphism of mono-amino acid repeats in androgen receptor and their regulatory role in health and disease.

Androgen receptor (AR) is a key member of nuclear hormone receptors with the longest intrinsically disordered N-terminal domain (NTD) in its protein family. There are four mono-amino acid repeats (polyQ1, polyQ2, polyG, and polyP) located within its NTD, of which two are polymorphic (polyQ1 and polyG). The length of both polymorphic repeats shows clinically important correlations with disease, especially with cancer and neurodegenerative diseases, as shorter and longer alleles exhibit significant differences in expression, activity and solubility.

A Novel Tandem-Tag Purification Strategy for Challenging Disordered Proteins.

Intrinsically disordered proteins (IDPs) lack well-defined 3D structures and can only be described as ensembles of different conformations. This high degree of flexibility allows them to interact promiscuously and makes them capable of fulfilling unique and versatile regulatory roles in cellular processes. These functional benefits make IDPs widespread in nature, existing in every living organism from bacteria and fungi to plants and animals.

Intrinsic protein disorder uncouples affinity from binding specificity.

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) of proteins often function by molecular recognition, in which they undergo induced folding. Based on prior generalizations, the idea prevails in the IDP field that due to the entropic penalty of induced folding, the major functional advantage associated with this binding mode is "uncoupling" specificity from binding strength. Nevertheless, both weaker binding and high specificity of IDPs/IDRs rest on limited experimental observations, making these assumptions more speculations than evidence-supported facts.

Biological colloids: Unique properties of membraneless organelles in the cell.

Biomolecular condensates are membraneless, intracellular organelles that form via liquid-liquid phase separation (LLPS) and have the ability to concentrate a wide range of molecules in the cellular milieu. These organelles are highly dynamic and play pivotal roles in cellular organization and physiology. Many studies also link the formation and misregulation of condensates to diseases such as neurodegenerative disorders and cancer.

A fish herpesvirus highlights functional diversities among Zα domains related to phase separation induction and A-to-Z conversion.

Zalpha (Zα) domains bind to left-handed Z-DNA and Z-RNA. The Zα domain protein family includes cellular (ADAR1, ZBP1 and PKZ) and viral (vaccinia virus E3 and cyprinid herpesvirus 3 (CyHV-3) ORF112) proteins. We studied CyHV-3 ORF112, which contains an intrinsically disordered region and a Zα domain.

Degron masking outlines degronons, co-degrading functional modules in the proteome.

Effective organization of proteins into functional modules (networks, pathways) requires systems-level coordination between transcription, translation and degradation. Whereas the cooperation between transcription and translation was extensively studied, the cooperative degradation regulation of protein complexes and pathways has not been systematically assessed. Here we comprehensively analyzed degron masking, a major mechanism by which cellular systems coordinate degron recognition and protein degradation.

F/YGG-motif is an intrinsically disordered nucleic-acid binding motif.

Heterogeneous nuclear ribonucleoproteins (hnRNP) function in RNA processing, have RNA-recognition motifs (RRMs) and intrinsically disordered, low-complexity domains (LCDs). While RRMs are drivers of RNA binding, there is only limited knowledge about the RNA interaction by the LCD of some hnRNPs. Here, we show that the LCD of hnRNPA2 interacts with RNA via an embedded Tyr/Gly-rich region which is a disordered RNA-binding motif.

DisProt in 2022: improved quality and accessibility of protein intrinsic disorder annotation.

The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%.

The role of ordered cooperative assembly in biomolecular condensates.

Biomolecular condensates, regardless of whether they exhibit liquid-like properties, are in many cases not fully amorphous, but instead exhibit partial degrees of local structure and order. Here, we discuss how ordered interactions may underlie the cooperative assembly and cellular function of a wide variety of partially ordered macromolecular assemblies.

"Protein" no longer means what it used to.

Every biologist knows that the word describes a group of macromolecules essential to sustain life on Earth. As biologists, we are invariably trained under a protein paradigm established since the early twentieth century. However, in recent years, the term unveiled itself as an euphemism to describe the overwhelming heterogeneity of these compounds.

Exploring Curated Conformational Ensembles of Intrinsically Disordered Proteins in the Protein Ensemble Database.

The Protein Ensemble Database (PED; https://proteinensemble.org/) is the major repository of conformational ensembles of intrinsically disordered proteins (IDPs). Conformational ensembles of IDPs are primarily provided by their authors or occasionally collected from literature, and are subsequently deposited in PED along with the corresponding structured, manually curated metadata.

Cellular Chaperone Function of Intrinsically Disordered Dehydrin ERD14.

Disordered plant chaperones play key roles in helping plants survive in harsh conditions, and they are indispensable for seeds to remain viable. Aside from well-known and thoroughly characterized globular chaperone proteins, there are a number of intrinsically disordered proteins (IDPs) that can also serve as highly effective protecting agents in the cells. One of the largest groups of disordered chaperones is the group of dehydrins, proteins that are expressed at high levels under different abiotic stress conditions, such as drought, high temperature, or osmotic stress.

DNA-binding domain as the minimal region driving RNA-dependent liquid-liquid phase separation of androgen receptor.

Androgen receptor (AR) is a nuclear hormone receptor that regulates the transcription of genes involved in the development of testis, prostate and the nervous system. Misregulation of AR is a major driver of prostate cancer (PC). The primary agonist of full-length AR is testosterone, whereas its splice variants, for example, AR-v7 implicated in cancer may lack a ligand-binding domain and are thus devoid of proper hormonal control.

Liquid-Liquid Phase Separation Enhances TDP-43 LCD Aggregation but Delays Seeded Aggregation.

Aggregates of TAR DNA-binding protein (TDP-43) are a hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although TDP-43 aggregates are an undisputed pathological species at the end stage of these diseases, the molecular changes underlying the initiation of aggregation are not fully understood. The aim of this study was to investigate how phase separation affects self-aggregation and aggregation seeded by pre-formed aggregates of either the low-complexity domain (LCD) or its short aggregation-promoting regions (APRs).