Biology subjects

Kalman, Z. E.

Publications and source records attributed to Kalman, Z. E..

9 recordsLinked to original sources

bioRxiv2026

Reliable prediction of short linear motifs in the human proteome

Short linear motifs (SLiMs) are small interaction modules within intrinsically disordered regions of proteins that interact with specific domains, and thereby regulate numerous biological processes. Their limited sequence information leads to frequent false positive hits in computational and experimental SLiM identification methods. We present SLiMMine, a deep learning-based method to identify SLiMs in the human proteome. By refining the annotations of known motif classes, we created a high-quality training dataset. Using protein embeddings and neural networks, SLiMMine reliably predicts novel SLiM candidates in known classes, eliminates ~80% of the pattern matching-based hits as false-positives, furthermore, it also functions as a discovery tool to find uncharacterized SLiMs based on optimal sequence environment. Finally, narrowing the broad interactor-domain definitions of known SLiM classes to specific human proteins enables more precise linking of predicted SLiMs to known protein-protein interactions. SLiMMine is available as a user-friendly, multipurpose web server at https://slimmine.pbrg.hu/.

bioinformatics↗

bioRxiv2025

Modulation of the internal dynamics of the Homer1 EVH1 domain by putative autism-associated mutations

The EVH1 domain of the Homer1 scaffold protein interacts with the proline-rich region of Shank3, forming a key network within the postsynaptic density. Two mutations in EVH1, M65I and S97L, were suggested to be associated with autism spectrum disorder. Combining experimental and computational investigations, we show here that neither the overall structure nor the partner binding properties of the mutants exhibit substantial changes relative to the wild type. Compared to the S97L variant, the M65I mutant exhibits larger chemical shift perturbations both upon the mutation itself and during partner binding, and also shows signs of thermal destabilization. Integration of computational and NMR investigations suggests that both mutations perturb the s-ms time scale internal motions of the EVH1 domain.

molecular biology↗

bioRxiv2025

Definition and discovery of tandem SH3-binding motifs interacting with members of the p47phox-related protein family

SH3 domains are widespread protein modules that mostly bind to proline-rich short linear motifs (SLiMs). Most known SH3 domain-motif interactions and canonical or non-canonical recognition specificities are described for individual SH3 domains. Although cooperation and coordinated motif binding between tandem SH3 domains has already been described for members of the p47phox-related protein family, individual cases have never been collected and analyzed collectively, which precluded the definition of the binding preferences and targeted discovery of further instances. Here, we apply an integrative approach that includes data collection, curation, bioinformatics analyses and state-of-the-art structure prediction methods to fill these gaps. We define the optimal binding preference of tandemly arranged SH3 domains as [PAVIL]PPR[PR][^DE][^DE], and propose potential new instances of this SLiM among the family members and their binding partners. Structure predictions suggest the possibility of a novel, reverse binding mode for certain motif instances. A search of the human proteome with the sequence signatures of SH3 tandemization and follow-up structure analyses suggest that SH3 tandemization could be specific for this family. In all, our comprehensive analysis of this unique SH3 binding mode enabled description of the binding preference and identification of novel interesting cases proposed for experimental validation.

molecular biology↗

bioRxiv2025

Structural modelling and dynamics of the full-length Homer1 multimer

Abstract/SummaryHomer proteins are modular scaffold molecules that constitute an integral part of the protein network within the postsynaptic density. Full-length Homer1 forms a large homotetramer via a long coiled coil region, and can interact with proline-rich target sequences with its globular EVH1 domain. Here we report an atomistic model of the full-length Homer1 tetramer along with the NMR solution structure of its EVH1 domain. Compared to the already available EVH1 structures, our NMR ensemble exhibits subtle differences, mostly in and around its partner binding region, suggesting the presence of ligand-induced conformational transitions. Molecular dynamics simulations of the long coiled coil reveal distinct regions with different stability and flexibility, with the N-terminal part of the coiled coil exhibiting the largest motions. Interestingly, this segment is highly conserved, pointing to the functional relevance of the observed dynamical features. Our results indicate previously unexplored aspects of the flexibility of the full-length Homer1 tetramer that might contribute to the dynamic rearrangements of the postsynaptic protein network linked to its functional transitions.

molecular biology↗

bioRxiv2024

Residual flexibility in the topologically constrained multivalent complex between the GKAP scaffold and LC8 hub proteins

Guanylate kinase-associated protein (GKAP) is a large postsynaptic scaffold protein bearing two closely spaced noncanonical binding sites for the bivalent dynein light chain LC8 hub protein. This might allow the formation of heterogeneous complexes with different sizes and topologies. Here, we show that a well-defined hexameric complex is formed, composed of 2 GKAP molecules and 2 LC8 dimers. Using NMR spectroscopy, we demonstrate that the LC8-binding segment of GKAP is intrinsically disordered and the flexibility of the linker region is largely retained even in the complex form. Molecular dynamics calculations suggest that besides the tightly bound residues, the hexamer also exhibits several dynamically interchanging interactions. The flanking regions of the two binding sites on GKAP exhibit different interaction patterns, hinting at additional contacts that might explain the fixed stoichiometry of the assembly. Our results demonstrate that constrained stoichiometry can coexist with substantial flexibility in a multivalent system.

molecular biology↗

bioRxiv2023

LeishMANIAdb: an integrative structural resource of Leishmania proteins

Leishmaniasis is a detrimental disease causing serious changes in quality of life and some forms 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 (PPIs). Here we present LeishMANIAdb, a database specifically designed to investigate how Leishmania virulence factors may interfere with host proteins. Since the secretomes of different Leishmania species are only partially characterized, we collected various experimental evidence and used computational predictions to identify Leishmania secreted proteins to generate a user-friendly unified web resource allowing users to access all information available on experimental and predicted secretomes. In addition, we manually annotated host-pathogen interactions of 211 proteins, and the localization/function of 3764 transmembrane (TM) proteins of different Leishmania species. We also enriched all proteins with automatic structural and functional predictions that can provide new insights in the molecular mechanisms of infection. Our database, available at https://leishmaniadb.ttk.hu may provide novel insights into Leishmania host-pathogen interactions and help to identify new therapeutic targets for this neglected disease.

bioinformatics↗

bioRxiv2021

PSINDB: A comprehensive database of postsynaptic protein-protein interactions

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 in this network, these data are mostly scattered in the literature or are stored in generic databases that are not designed to display aspects which are fundamental to understanding postsynaptic functions. To overcome these limitations we collected postsynaptic protein-protein interactions (PPIs) together with 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. PSINDB includes tens of thousands of binding regions together with structural features mediating and regulating the formation of PPIs, annotated with detailed experimental information about each interaction. PSINDB is expected to be useful for numerous aspects of molecular neurobiology research, from experiment design to network and systems biology-based modeling and analysis of changes in the protein network upon various stimuli. PSINDB is available at http://psindb.itk.ppke.hu/.

bioinformatics↗

bioRxiv2021

A preliminary study on the cistrome of human postsynaptic density from an evolutionary and network-based perspective

The postsynaptic density (PSD) is a neuronal organelle that consists of thousands of protein complexes, having a role in signal transduction. The emergence of the complexes is dependent on the presence of proteins provided by gene expression. In this research we used Chip-seq data supported by protein level information. We developed a pipeline using data from five neuronal transcription factors, which reduces the false-positive hits of identified binding sites. In addition we found correlation between co-regulation and protein complex formation. The developed method paves the way for a future for large scale analysis utilizing a more comprehensive set of transcription factors.

bioinformatics↗

bioRxiv2020

Distribution of disease-causing germline mutations in coiled-coils suggests essential 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 -helical structures responsible for a diverse range of functions, but most importantly, they facilitate the structural organization of macromolecular scaffolds via oligomerization. In this study, we analyzed a comprehensive set of disease-associated germline mutations in coiled-coil structures. Our results highlight the essential role of residues near the N-terminal part of coiled-coil regions, possibly critical for superhelix assembly and folding in some cases. We also show that coiled-coils of different oligomerization states exhibit characteristically distinct patterns of disease-causing mutations. Our study provides structural and functional explanations on how disease emerges through the mutation of these structural motifs.

bioinformatics↗