A sequence ‐based model for identifying proteins undergoing liquid–liquid phase separation/forming fibril aggregates via machine learning
AbstractLiquid –liquid phase separation (LLPS) and the solid aggregate (also referred to as amyloid aggregates) formation of proteins, have gained significant attention in recent years due to their associations with various physiological and pathological processes in living organisms. The systematic investigatio n of the differences and connections between proteins undergoing LLPS and those forming amyloid fibrils at the sequence level has not yet been explored. In this research, we aim to address this gap by comparing the two types of proteins across 36 features using collected data available currently. Th e statistical...
Source: Protein Science - February 21, 2024 Category: Biochemistry Authors: Shaofeng Liao,
Yujun Zhang,
Xinchen Han,
Tinglan Wang,
Xi Wang,
Qinglin Yan,
Qian Li,
Yifei Qi,
Zhuqing Zhang Tags: RESEARCH ARTICLE Source Type: research
Protein structure accuracy estimation using geometry ‐complete perceptron networks
AbstractEstimating the accuracy of protein structural models is a critical task in protein bioinformatics. The need for robust methods in the estimation of protein model accuracy (EMA) is prevalent in the field of protein structure prediction, where computationally-predicted structures need to be screened rapidly for the reliability of the positions predicted for each of their amino acid residues and their overall quality. Current methods proposed for EMA are either coupled tightly to existing protein structure prediction methods or evaluate protein structures without sufficiently leveraging the rich, geometric information...
Source: Protein Science - February 21, 2024 Category: Biochemistry Authors: Alex Morehead,
Jian Liu,
Jianlin Cheng Tags: TOOLS FOR PROTEIN SCIENCE Source Type: research
VWD domain stabilization by autocatalytic Asp ‐Pro cleavage
In this study, we investigated the structural and biophysical consequences of Asp-Pro peptide cleavage in a representative FCGBP VWD domain. We found that endogenous Asp-Pro cleavage increases the resistance of the domain to exogenous proteolytic degradation. Tertiary structural interactions made by the newly generated chain termini, as revealed by a crystal structure of an FCGBP segment containing the VWD domain, may explain this observation. Notably, the Gly-Asp peptide bond, upstream of the cleavage site, assumed thecis configuration in the structure. In addition to these local features of the cleavage site, a global or...
Source: Protein Science - February 21, 2024 Category: Biochemistry Authors: Noa Yeshaya,
Prashant Kumar Gupta,
Orly Dym,
David Morgenstern,
Dan Thomas Major,
Deborah Fass Tags: RESEARCH ARTICLE Source Type: research
Structural insights into peptidoglycan glycosidase EtgA binding to the inner rod protein EscI of the type III secretion system via a designed EscI ‐EtgA fusion protein
AbstractBacteria express lytic enzymes such as glycosidases, which have potentially self-destructive peptidoglycan (PG)-degrading activity and, therefore, require careful regulation in bacteria. The PG glycosidase EtgA is regulated by localization to the assembling type III secretion system (T3SS), generating a hole in the PG layer for the T3SS to reach the outer membrane. The EtgA localization was found to be mediated via EtgA interacting with the T3SS inner rod protein EscI. To gain structural insights into the EtgA recognition of EscI, we determined the 2.01 Å resolution structure of an EscI (51–87)-linker-EtgA fu...
Source: Protein Science - February 21, 2024 Category: Biochemistry Authors: J. Boorman,
X. Zeng,
J. Lin,
F. van den Akker Tags: RESEARCH ARTICLE Source Type: research
Protective roles of highly conserved motif 1 in tardigrade cytosolic ‐abundant heat soluble protein in extreme environments
AbstractTardigrades are remarkable microscopic animals that survive harsh conditions such as desiccation and extreme temperatures. Tardigrade-specific intrinsically disordered proteins (TDPs) play an essential role in the survival of tardigrades in extreme environments. Cytosolic-abundant heat soluble (CAHS) protein, a key TDP, is known to increase desiccation tolerance and to protect the activity of several enzymes under dehydrated conditions. However, the function and properties of each CAHS domain have not yet been elucidated in detail. Here, we aimed to elucidate the protective role of highly conserved motif 1 of CAHS ...
Source: Protein Science - February 16, 2024 Category: Biochemistry Authors: Donguk Kang,
Min June Yang,
Hwan Kim,
Chin ‐Ju Park Tags: RESEARCH ARTICLE Source Type: research
The catalytic domain of free or ligand bound histone deacetylase 4 occurs in solution predominantly in closed conformation
AbstractHuman histone deacetylase 4 (HDAC4) is a key epigenetic regulator involved in a number of important cellular processes. This makes HDAC4 a promising target for the treatment of several cancers and neurodegenerative diseases, in particular Huntington's disease. HDAC4 is highly regulated by phosphorylation and oxidation, which determine its nuclear or cytosolic localization, and exerts its function through multiple interactions with other proteins, forming multiprotein complexes of varying composition. The catalytic domain of HDAC4 is known to interact with the SMRT/NCOR corepressor complex when the structural zinc-b...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Markus Schweipert,
Thomas Nehls,
Anton Fr ühauf,
Cecilé Debarnot,
Adarsh Kumar,
Stefan Knapp,
Frederik Lermyte,
Franz‐Josef Meyer‐Almes Tags: RESEARCH ARTICLE Source Type: research
The C ‐terminus is essential for the stability of the mycobacterial channel protein MspA
In this study, we show that mutation and deletion of methionine 183 in the highly conserved C-terminus of MspA and mutation of the conserved tryptophan 40 lead to a complete loss of protein in heat extracts ofM. smegmatis. Swapping these residues partially restores the heat stability of MspA indicating that methionine 183 and tryptophan 40 form a conserved sulfur- π electron interaction, which stabilizes the MspA monomer. Flow cytometry showed that all MspA mutants are surface-accessible demonstrating that oligomerization and membrane integration inM. smegmatis are not affected. Thus, the conserved C-terminus of MspA is e...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Mikhail Pavlenok,
Rashmi Ravindran Nair,
R. Curtis Hendrickson,
Michael Niederweis Tags: RESEARCH ARTICLE Source Type: research
Key interaction networks: Identifying evolutionarily conserved non ‐covalent interaction networks across protein families
AbstractProtein structure (and thus function) is dictated by non-covalent interaction networks. These can be highly evolutionarily conserved across protein families, the members of which can diverge in sequence and evolutionary history. Here we present KIN, a tool to identify and analyze conserved non-covalent interaction networks across evolutionarily related groups of proteins. KIN is available for download under a GNU General Public License, version 2, fromhttps://www.github.com/kamerlinlab/KIN. KIN can operate on experimentally determined structures, predicted structures, or molecular dynamics trajectories, providing i...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Dariia Yehorova,
Rory M. Crean,
Peter M. Kasson,
Shina C. L. Kamerlin Tags: TOOLS FOR PROTEIN SCIENCE Source Type: research
Crystal structure of the tegument protein UL82 (pp71) from human cytomegalovirus
AbstractHuman cytomegalovirus (HCMV) is an opportunistic pathogen that infects a majority of the world population. It may cause severe disease in immunocompromised people and lead to pregnancy loss or grave disabilities of the fetus upon congenital infection. For effective replication and lifelong persistence in its host, HCMV relies on diverse functions of its tegument protein UL82, also known as pp71. Up to now, little is known about the molecular mechanisms underlying the multiple functions of this crucial viral protein. Here, we describe the X-ray structure of full-length UL82 to a resolution of 2.7 Å. A single pol...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Jan Eberhage,
Ian P. Bresch,
Ramya Ramani,
Niklas Viohl,
Thalea Buchta,
Christopher L. Rehfeld,
Petra Hinse,
Thomas F. Reubold,
Melanie M. Brinkmann,
Susanne Eschenburg Tags: RESEARCH ARTICLE Source Type: research
A PDZ scaffolding/CaM ‐mediated pathway in Cryptochrome signaling
In this study, we demonstrate that human CRY2 (hCRY2) forms a complex with the large, modular scaffolding protein known as Multi-PDZ Domain Protein 1 (MUPP1). This interaction is facilitated by the calcium-binding protein Calmodulin (CaM) in a calcium-dependent manner. Our findings suggest a novel cooperative mechanism for the regulation of mammalian cryptochromes, mediated by calcium ions (Ca2+) and CaM. We propose that this Ca2+/CaM-mediated signaling pathway may be an evolutionarily conserved mechanism that has been maintained fromDrosophila to mammals, most likely in relation to its potential role in the broader contex...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Massimo Bellanda,
Milena Damulewicz,
Barbara Zambelli,
Elisa Costanzi,
Francesco Gregoris,
Stefano Mammi,
Silvio C. E. Tosatto,
Rodolfo Costa,
Giovanni Minervini,
Gabriella M. Mazzotta Tags: RESEARCH ARTICLE Source Type: research
Identification of small ‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening
AbstractUBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin-conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug-like small molecules. Here, we performed fragment screening using19F-nuclear magnetic resonance (NMR) and validated the hits with1H-15N-heteronuclear single quantum coherence (HSQC) experiment and X-ray crystallographic studies. The cocrystal structures obtained revealed the binding modes of the hit fragments and allowed for the characteriz...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Yong Yao Loh,
Jothi Anantharajan,
Qiwei Huang,
Weijun Xu,
Justina Fulwood,
Hui Qi Ng,
Elizabeth Yihui Ng,
Chong Yu Gea,
Meng Ling Choong,
Qian Wen Tan,
Xiaoying Koh,
Wan Hsin Lim,
Kassoum Nacro,
Joseph Cherian,
Nithya Baburajendran,
Zhiyuan Tags: RESEARCH ARTICLE Source Type: research
Accounting for nonuniformity of bulk ‐solvent: A mosaic model
AbstractA flat mask-based model is almost universally used in macromolecular crystallography to account for disordered (bulk) solvent. This model assumes any voxel of the crystal unit cell that is not occupied by the atomic model is occupied by the solvent. The properties of this solvent are assumed to be exactly the same across the whole volume of the unit cell. While this is a reasonable approximation in practice, there are a number of scenarios where this model becomes suboptimal. In this work, we enumerate several of these scenarios and describe a new generalized approach to modeling the bulk-solvent which we refer to ...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Pavel V. Afonine,
Paul D. Adams,
Oleg V. Sobolev,
Alexandre G. Urzhumtsev Tags: TOOLS FOR PROTEIN SCIENCE Source Type: research
Controlling the incorporation of fluorinated amino acids in human cells and its structural impact
This study offers a predictive model of the FAA incorporation efficiency and provides a framework for controlling protein fluorination in mammalian expression systems. (Source: Protein Science)
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Azzurra Costantino,
Lan B. T. Pham,
Letizia Barbieri,
Vito Calderone,
Gili Ben ‐Nissan,
Michal Sharon,
Lucia Banci,
Enrico Luchinat Tags: METHODS AND APPLICATIONS Source Type: research
Exploring the dynamics and structure of PpiB in living Escherichia coli cells using electron paramagnetic resonance spectroscopy
We report a significant decrease in the dynamics induced by the cellular environment for two chosen labeling positions. These changes could not be reproduced by adding crowding agents and cell extracts. Concomitantly, we report a broadening of the distance distribution inE. coli, determined by Gd(III) –Gd(III) DEER measurements, as compared with solution and human HeLa cells. This suggests an increase in the number of PpiB conformations present inE. coli cells, possibly due to interactions with other cell components, which also contributes to the reduction in mobility and suggests the presence of a quinary structure. (So...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Yasmin Ben ‐Ishay,
Yoav Barak,
Akiva Feintuch,
Olivier Ouari,
Annalisa Pierro,
Elisabetta Mileo,
Xun‐Cheng Su,
Daniella Goldfarb Tags: RESEARCH ARTICLE Source Type: research
Protein ensemble modeling and analysis with MMMx
AbstractProteins, especially of eukaryotes, often have disordered domains and may contain multiple folded domains whose relative spatial arrangement is distributed. The MMMx ensemble modeling and analysis toolbox (https://github.com/gjeschke/MMMx) can support the design of experiments to characterize the distributed structure of such proteins, starting from AlphaFold2 predictions or folded domain structures. Weak order can be analyzed with reference to a random coil model or to peptide chains that match the residue-specific Ramachandran angle distribution of the loop regions and are otherwise unrestrained. The deviation of...
Source: Protein Science - February 15, 2024 Category: Biochemistry Authors: Gunnar Jeschke Tags: TOOLS FOR PROTEIN SCIENCE Source Type: research
