MFIB 2.0: a major update of the database of protein complexes formed by mutual folding of the constituting protein chains.

While the majority of proteins with available structures are able to fold independently and mediate interactions only after acquiring their folded state, a subset of the known protein complexes contains protein chains that are intrinsically disordered in isolation. The Mutual Folding Induced by Binding (MFIB) database collects and classifies protein complexes, wherein all constituent protein chains would be unstable/disordered in isolation but fold into a well-defined 3D complex structure upon binding. This phenomenon is often termed as cooperative folding and binding or mutual synergistic folding (MSF).

Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents.

The pathogenic, tropical Leishmania flagellates belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Unfortunately, they are poorly understood from a molecular biology perspective, making development of mechanistically novel and selective drugs difficult. Here, we explore three functionally critical targeting short linear motif systems as well as their receptors in depth, using a combination of structural modeling, evolutionary sequence divergence and deep learning.

How AlphaFold2 shaped the structural coverage of the human transmembrane proteome.

AlphaFold2 (AF2) provides a 3D structure for every known or predicted protein, opening up new prospects for virtually every field in structural biology. However, working with transmembrane protein molecules pose a notorious challenge for scientists, resulting in a limited number of experimentally determined structures. Consequently, algorithms trained on this finite training set also face difficulties.

ELM-the Eukaryotic Linear Motif resource-2024 update.

Short Linear Motifs (SLiMs) are the smallest structural and functional components of modular eukaryotic proteins. They are also the most abundant, especially when considering post-translational modifications. As well as being found throughout the cell as part of regulatory processes, SLiMs are extensively mimicked by intracellular pathogens.

LeishMANIAdb: a comparative resource for Leishmania proteins.

Leishmaniasis is a detrimental disease causing serious changes in quality of life and some forms can lead to death. The disease is spread by the parasite Leishmania transmitted by sandfly vectors and their primary hosts are vertebrates including humans. The pathogen penetrates host cells and secretes proteins (the secretome) to repurpose cells for pathogen growth and to alter cell signaling via host-pathogen protein-protein interactions).

UniTmp: unified resources for transmembrane proteins.

The UNIfied database of TransMembrane Proteins (UniTmp) is a comprehensive and freely accessible resource of transmembrane protein structural information at different levels, from localization of protein segments, through the topology of the protein to the membrane-embedded 3D structure. We not only annotated tens of thousands of new structures and experiments, but we also developed a new system that can serve these resources in parallel. UniTmp is a unified platform that merges TOPDB (Topology Data Bank of Transmembrane Proteins), TOPDOM (database of conservatively located domains and motifs in proteins), PDBTM (Protein Data Bank of Transmembrane Proteins) and HTP (Human Transmembrane Proteome) databases and provides interoperability between the incorporated resources and an easy way to keep them regularly updated.

TmAlphaFold database: membrane localization and evaluation of AlphaFold2 predicted alpha-helical transmembrane protein structures.

AI-driven protein structure prediction, most notably AlphaFold2 (AF2) opens new frontiers for almost all fields of structural biology. As traditional structure prediction methods for transmembrane proteins were both complicated and error prone, AF2 is a great help to the community. Complementing the relatively meager number of experimental structures, AF2 provides 3D predictions for thousands of new alpha-helical membrane proteins.

PSINDB: the postsynaptic protein-protein interaction database.

The postsynaptic region is the receiving part of the synapse comprising thousands of proteins forming an elaborate and dynamically changing network indispensable for the molecular mechanisms behind fundamental phenomena such as learning and memory. Despite the growing amount of information about individual protein-protein interactions (PPIs) in this network, these data are mostly scattered in the literature or stored in generic databases that are not designed to display aspects that are fundamental to the understanding of postsynaptic functions. To overcome these limitations, we collected postsynaptic PPIs complemented by a high amount of detailed structural and biological information and launched a freely available resource, the Postsynaptic Interaction Database (PSINDB), to make these data and annotations accessible.

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%.

MemDis: Predicting Disordered Regions in Transmembrane Proteins.

Transmembrane proteins (TMPs) play important roles in cells, ranging from transport processes and cell adhesion to communication. Many of these functions are mediated by intrinsically disordered regions (IDRs), flexible protein segments without a well-defined structure. Although a variety of prediction methods are available for predicting IDRs, their accuracy is very limited on TMPs due to their special physico-chemical properties.

The Eukaryotic Linear Motif resource: 2022 release.

Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for the study of motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository of manually curated, experimentally validated short linear motifs (SLiMs). An increasing number of SLiM-mediated interactions are discovered each year and keeping the resource up-to-date continues to be a great challenge.

PolarProtPred: predicting apical and basolateral localization of transmembrane proteins using putative short linear motifs and deep learning.

Motivation: Cell polarity refers to the asymmetric organization of cellular components in various cells. Epithelial cells are the best-known examples of polarized cells, featuring apical and basolateral membrane domains. Mounting evidence suggests that short linear motifs play a major role in protein trafficking to these domains, although the exact rules governing them are still elusive.

PolarProtDb: A Database of Transmembrane and Secreted Proteins showing Apical-Basal Polarity.

Most cells in multicellular organisms are somehow asymmetric, polarized: maintaining separate membrane domains. Typical examples are the epithelial cells (apical-basal polarization), neurons (dendritic-axonal domains), or migratory cells (with a leading and a trailing edge). Here we present the most comprehensive database containing experimentally verified mammalian proteins that display polarized sorting or secretion, focusing on epithelial polarity.

Distribution of disease-causing germline mutations in coiled-coils implies an important role of their N-terminal region.

Next-generation sequencing resulted in the identification of a huge number of naturally occurring variations in human proteins. The correct interpretation of the functional effects of these variations necessitates the understanding of how they modulate protein structure. Coiled-coils are α-helical structures responsible for a diverse range of functions, but most importantly, they facilitate the structural organization of macromolecular scaffolds via oligomerization.

PlaToLoCo: the first web meta-server for visualization and annotation of low complexity regions in proteins.

Low complexity regions (LCRs) in protein sequences are characterized by a less diverse amino acid composition compared to typically observed sequence diversity. Recent studies have shown that LCRs may co-occur with intrinsically disordered regions, are highly conserved in many organisms, and often play important roles in protein functions and in diseases. In previous decades, several methods have been developed to identify regions with LCRs or amino acid bias, but most of them as stand-alone applications and currently there is no web-based tool which allows users to explore LCRs in protein sequences with additional functional annotations.

Sequence and Structure Properties Uncover the Natural Classification of Protein Complexes Formed by Intrinsically Disordered Proteins via Mutual Synergistic Folding.

Intrinsically disordered proteins mediate crucial biological functions through their interactions with other proteins. Mutual synergistic folding (MSF) occurs when all interacting proteins are disordered, folding into a stable structure in the course of the complex formation. In these cases, the folding and binding processes occur in parallel, lending the resulting structures uniquely heterogeneous features.

Sequential, Structural and Functional Properties of Protein Complexes Are Defined by How Folding and Binding Intertwine.

Intrinsically disordered proteins (IDPs) fulfill critical biological roles without having the potential to fold on their own. While lacking inherent structure, the majority of IDPs do reach a folded state via interaction with a protein partner, presenting a deep entanglement of the folding and binding processes. Protein disorder has been recognized as a major determinant in several properties of proteins, such as sequence, adopted structure upon binding and function.

Occurrence of Ordered and Disordered Structural Elements in Postsynaptic Proteins Supports Optimization for Interaction Diversity.

The human postsynaptic density is an elaborate network comprising thousands of proteins, playing a vital role in the molecular events of learning and the formation of memory. Despite our growing knowledge of specific proteins and their interactions, atomic-level details of their full three-dimensional structure and their rearrangements are mostly elusive. Advancements in structural bioinformatics enabled us to depict the characteristic features of proteins involved in different processes aiding neurotransmission.

Structural Principles Governing Disease-Causing Germline Mutations.

Advancements in sequencing in the past decades enabled not only the determination of the human proteome but also the identification of a large number of genetic variations in the human population. The phenotypic effects of these mutations range from neutral for polymorphisms to severe for some somatic mutations. Disease-causing germline mutations (DCMs) represent a special and largely understudied class with relatively weak phenotypes.

Identification of Extracellular Segments by Mass Spectrometry Improves Topology Prediction of Transmembrane Proteins.

Transmembrane proteins play crucial role in signaling, ion transport, nutrient uptake, as well as in maintaining the dynamic equilibrium between the internal and external environment of cells. Despite their important biological functions and abundance, less than 2% of all determined structures are transmembrane proteins. Given the persisting technical difficulties associated with high resolution structure determination of transmembrane proteins, additional methods, including computational and experimental techniques remain vital in promoting our understanding of their topologies, 3D structures, functions and interactions.

TSTMP: target selection for structural genomics of human transmembrane proteins.

The TSTMP database is designed to help the target selection of human transmembrane proteins for structural genomics projects and structure modeling studies. Currently, there are only 60 known 3D structures among the polytopic human transmembrane proteins and about a further 600 could be modeled using existing structures. Although there are a great number of human transmembrane protein structures left to be determined, surprisingly only a small fraction of these proteins have 'selected' (or above) status according to the current version the TargetDB/TargetTrack database.

TOPDOM: database of conservatively located domains and motifs in proteins.

Unlabelled: The TOPDOM database-originally created as a collection of domains and motifs located consistently on the same side of the membranes in α-helical transmembrane proteins-has been updated and extended by taking into consideration consistently localized domains and motifs in globular proteins, too. By taking advantage of the recently developed CCTOP algorithm to determine the type of a protein and predict topology in case of transmembrane proteins, and by applying a thorough search for domains and motifs as well as utilizing the most up-to-date version of all source databases, we managed to reach a 6-fold increase in the size of the whole database and a 2-fold increase in the number of transmembrane proteins.

Availability And Implementation: TOPDOM database is available at http://topdom.

A conserved charged single α-helix with a putative steric role in paraspeckle formation.

Paraspeckles are subnuclear particles involved in the regulation of mRNA expression. They are formed by the association of DBHS family proteins and the NEAT1 long noncoding RNA. Here, we show that a recently identified structural motif, the charged single α-helix, is largely conserved in the DBHS family.

Disordered regions in transmembrane proteins.

The functions of transmembrane proteins in living cells are widespread; they range from various transport processes to energy production, from cell-cell adhesion to communication. Structurally, they are highly ordered in their membrane-spanning regions, but may contain disordered regions in the cytosolic and extra-cytosolic parts. In this study, we have investigated the disordered regions in transmembrane proteins by a stringent definition of disordered residues on the currently available largest experimental dataset, and show a significant correlation between the spatial distributions of positively charged residues and disordered regions.

The human transmembrane proteome.

Background: Transmembrane proteins have important roles in cells, as they are involved in energy production, signal transduction, cell-cell interaction, cell-cell communication and more. In human cells, they are frequently targets for pharmaceuticals; therefore, knowledge about their properties and structure is crucial. Topology of transmembrane proteins provide a low resolution structural information, which can be a starting point for either laboratory experiments or modelling their 3D structures.