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Protein Science

J V Rodrigues, C B Ogbunugafor, D L Hartl, E I Shakhnovich
While reverse genetics and functional genomics have long affirmed the role of individual mutations in determining protein function, there have been fewer studies addressing how larger-scaled changes in protein sequences, such as in entire modular segments, influence protein function and evolution. Given how recombination can reassort protein sequences, these types of changes may play an underappreciated role in how novel protein functions evolve in nature. Such studies could aid our understanding of whether certain organismal phenotypes related to protein function-such as growth in the presence or absence of an antibiotic-are robust with respect to the identity of certain modular segments...
May 16, 2019: Protein Science
Valentina L Kouznetsova, Alex Tchekanov, Xiaoming Li, Xiaowen Yan, Igor F Tsigelny
Numerous molecular processes conduct epigenetic regulation of protein transcription to maintain cell specification. In this review, we discuss molecular mechanisms of the Polycomb group (PcG) of proteins and its enzymatic role in epigenetics. More specifically, we focus on the Polycomb repressive complex 2 (PRC2) and the effects of its repressive marker. We have compiled information regarding the biological structure and how that impacts the stability of the complex. In addition, we examined functions of the individual core proteins of PRC2 in relation to the accessory proteins that interact with the complex...
May 16, 2019: Protein Science
Constance J Jeffery
In the cell, expression levels, allosteric modulators, post-translational modifications, sequestration, and other factors can affect the level of protein function. For moonlighting proteins, cellular factors like these can also affect the kind of protein function. This minireview discusses examples of moonlighting proteins that illustrate how a single protein can have different functions in different cell types, in different intracellular locations, or under varying cellular conditions. This variability in the kind of protein activity, added to the variability in the amount of protein activity, contributes to the difficulty in predicting the behavior of proteins in the cell...
May 14, 2019: Protein Science
Jeremy A Anderson, Andrea N Loes, Grace L Waddell, Michael J Harms
Toll-like receptor 4 (TLR4) is a critical innate immune protein that activates inflammation in response to extracellular cues. Much of the work to understand how the protein works in humans has been done using mouse models. Although human and mouse TLR4 have many shared features, they have also diverged significantly since their last common ancestor, acquiring 277 sequence differences. Functional differences include the extent of ligand-independent activation, whether lipid IVa acts as an antagonist or agonist, and the relative species cross-compatibility of their MD-2 cofactor...
May 10, 2019: Protein Science
Takuya Tomita, Andreas Matouschek
Proteins in the cell have to be eliminated once their function is no longer desired or they become damaged. Most regulated protein degradation is achieved by a large enzymatic complex called the proteasome. Many proteasome substrates are targeted for degradation by the covalent attachment of ubiquitin molecules. Ubiquitinated proteins can be bound by the proteasome, but for proteolysis to occur the proteasome needs to find a disordered tail somewhere in the target at which it initiates degradation. The initiation step contributes to the specificity of proteasomal degradation...
May 10, 2019: Protein Science
Aaron P Chum, Sophie R Shoemaker, Patrick J Fleming, Karen G Fleming
SurA, Skp, FkpA and DegP constitute a chaperone network that ensures biogenesis of outer membrane proteins (OMP)s in Gram-negative bacteria. Both Skp and FkpA are holdases that prevent the self-aggregation of unfolded OMPs, whereas SurA accelerates folding and DegP is a protease. None of these chaperones is essential, and we address here how functional plasticity is manifested in nine known null strains. Using a comprehensive computational model of this network termed OMPBioM, our results suggest that a threshold level of steady state holdase occupancy by chaperones is required, but the cell is agnostic to the specific holdase molecule fulfilling this function...
May 10, 2019: Protein Science
Mingjie Han, Sanhui Liao, Peng Xiong, Xiaoqun Zhou, Quan Chen, Haiyan Liu
Computationally designed proteins of high stability provide specimen in addition to natural proteins for the study of sequence-structure stability relationships at the very high end of protein stability spectrum. The melting temperature of E_1r26, a protein we previously designed using the ABACUS (A Backbone-based Amino aCid Usage Survey) sequence design program, is above 110 °C, more than 50 °C higher than that of the natural thioredoxin protein whose backbone (PDB ID 1r26) has been used as the design target...
May 10, 2019: Protein Science
Kristine Faye R Pobre, David L Powers, Kingshuk Ghosh, Lila M Gierasch, Evan T Powers
The effect of mutations in individual proteins on protein homeostasis, or "proteostasis", can in principle depend on the mutations' effects on the thermodynamics or kinetics of folding, or both. Here, we explore this issue using a computational model of in vivo protein folding that we call FoldEcoSlim. Our model predicts that kinetic vs. thermodynamic control of mutational effects on proteostasis hinges on the relationship between how fast a protein's folding reaction reaches equilibrium and a critical time scale that characterizes the lifetime of a protein in a cell: for rapidly dividing bacteria, this time scale is that of cell division; for proteins that are produced in heterologous expression systems, this time scale is the amount of time before the protein is harvested; for proteins that are synthesized in and then exported from the eukaryotic endoplasmic reticulum, this time scale is that of protein secretion, etc...
May 10, 2019: Protein Science
Megan L Machek, Halie A Sonnenschein, Sasha-Kaye I Graham, Flowreen Shikwana, Seung-Hwan L Kim, Selena Garcia-Dubar, Ian D Minzer, Ryan Wey, Jessica K Bell
Suppressor of IKKepsilon (SIKE) is a 207 residue protein that is implicated in the TLR3-TANK binding kinase 1-mediated response to viral infection. SIKE's function in this pathway is unknown, but SIKE forms interactions with two distinct cytoskeletal proteins, α-actinin and tubulin, and SIKE knockout reduces cell migration. As structure informs function and in the absence of solved structural homologs, our studies were directed toward creating a structural model of SIKE through biochemical and biophysical characterization to probe and interrogate SIKE function...
May 10, 2019: Protein Science
Shannon L Speer, Alex J Guseman, Jon B Patteson, Brandie M Ehrmann, Gary J Pielak
The cellular environment is dynamic and complex, involving thousands of different macromolecules with total concentrations of hundreds of grams per liter. However, most biochemistry is conducted in dilute buffer where the concentration of macromolecules is less than 10 g/L. High concentrations of macromolecules affect protein stability, function and protein complex formation, but to understand these phenomena fully we need to know the concentration of the test protein in cells. Here, we quantify the concentration of an overexpressed recombinant protein, a variant of the B1 domain of protein G (GB1), in Tuner (DE3)™ Escherichia coli cells as a function of inducer concentration...
May 4, 2019: Protein Science
Elizabeth C Duran, Aaron L Lucius
E. coli ClpA is a AAA+ (ATPase Associated with diverse cellular Activities) chaperone that catalyzes the ATP-dependent unfolding and translocation of substrate proteins targeted for degradation by a protease, ClpP. ClpA hexamers associate with one or both ends of ClpP tetradecamers to form ClpAP complexes. Each ClpA protomer contains two nucleotide binding sites, NBD1 and NBD2, and self-assembly into hexamers is thermodynamically linked to nucleotide binding. Despite a number of studies aimed at characterizing ClpA and ClpAP-catalyzed substrate unfolding and degradation, respectively, to date the field is unable to quantify the concentration of ClpA hexamers available to interact with ClpP for any given nucleotide and total ClpA concentration...
May 4, 2019: Protein Science
Danny Schildknegt, Naomi Lodder, Abhinav Pandey, Maarten Egmond, Florentina Pena, Ineke Braakman, Peter van der Sluijs
The Canopy (CNPY) family consists of four members predicted to be soluble proteins localized to the endoplasmic reticulum (ER). They are involved in a wide array of processes, including angiogenesis, cell adhesion and host defense. CNPYs are thought to do so via regulation of secretory transport of a diverse group of proteins, such as IgM, Growth Factor Receptors, Toll-Like Receptors and the Low-Density Lipoprotein Receptor. Thus far, a comparative analysis of the mammalian CNPY family is missing. Bioinformatic analysis shows that mammalian CNPYs, except the CNPY1 homolog, have N-terminal signal sequences and C-terminal ER-retention signals and that mammals have an additional member CNPY5, also known as pERp1/MZB1...
May 3, 2019: Protein Science
Lynley M Doonan, Christopher J Guerriero, G Michael Preston, Teresa M Buck, Netaly Khazanov, Edward A Fisher, Hanoch Senderowitz, Jeffrey L Brodsky
Misfolded proteins in the endoplasmic reticulum (ER) are selected for ER-associated degradation (ERAD). More than 60 disease-associated proteins are substrates for the ERAD pathway due to the presence of missense or nonsense mutations. In yeast, the Hsp104 molecular chaperone disaggregates detergent-insoluble ERAD substrates, but the spectrum of disease-associated ERAD substrates that may be aggregation-prone is unknown. To determine if Hsp104 recognizes aggregation-prone ERAD substrates associated with human diseases, we developed yeast expression systems for a hydrophobic lipid-binding protein, apolipoprotein B (ApoB), along with a chimeric protein harboring a nucleotide binding domain from the cystic fibrosis transmembrane conductance regulator (CFTR) into which disease-causing mutations were introduced...
May 3, 2019: Protein Science
Brian W Matthews
No abstract text is available yet for this article.
April 26, 2019: Protein Science
Lei Li, Shuang Chen, Zhichao Miao, Yang Liu, Xu Liu, ZhiXiong Xiao, Yang Cao
The remarkable progress in cancer immunotherapy in recent years has led to the heat of great development for therapeutic antibodies. Antibody numbering, which standardizes a residue index at each position of an antibody variable domain, is an important step in immunoinformatic analysis. It provides an equivalent index for the comparison of sequences or structures, which is particularly valuable for antibody modeling and engineering. However, due to the extremely high diversity of antibody sequences, antibody numbering tools cannot work in all cases...
April 24, 2019: Protein Science
Lynda Truong, Adrian R Ferré-D'Amaré
The explosion in genome-wide sequencing has revealed that non-coding RNAs are ubiquitous and highly conserved in biology. New molecular tools are needed for their study in live cells. Fluorescent RNA-small molecule complexes have emerged as powerful counterparts to fluorescent proteins, which are well established, universal tools in the study of proteins in cell biology. No naturally fluorescent RNAs are known; all current fluorescent RNA tags are in vitro evolved or engineered molecules that bind a conditionally fluorescent small molecule and turn on its fluorescence by up to 2000-fold...
April 24, 2019: Protein Science
Catherine A Royer
No abstract text is available yet for this article.
April 23, 2019: Protein Science
Yiqing Yang, Mihiravi Gunasekara, Shaima Muhammednazaar, Zhen Li, Heedeok Hong
AAA+ proteases utilize ATP hydrolysis to actively unfold native or misfolded proteins and translocate them into a protease chamber for degradation. This basic mechanism yields diverse cellular consequences, including the removal of misfolded proteins, control of regulatory circuits and remodeling of protein conformation. Among various bacterial AAA+ proteases, FtsH is only membrane-integrated and plays a key role in membrane protein quality control. Previously, we have shown that FtsH has substantial unfoldase activity for degrading membrane proteins overcoming a dual energetic burden of substrate unfolding and membrane dislocation...
April 22, 2019: Protein Science
Ronnie O Frederick, Miyoshi Haruta, Marco Tonelli, Woonghee Lee, Gabriel Cornilescu, Claudia C Cornilescu, Michael R Sussman, John L Markley
We report the recombinant preparation from Escherichia coli cells of samples of two closely related, small, secreted cysteine-rich plant peptides: Rapid ALkalinization Factor-1 (RALF1) and Rapid ALkalinization Factor-8 (RALF8). Purified samples of the native sequence of RALF8 exhibited well-resolved NMR spectra and also biological activity through interaction with a plant receptor kinase, cytoplasmic calcium mobilization, and in vivo root growth suppression. By contrast, RALF1 could only be isolated from inclusion bodies as a construct containing an N-terminal His-tag; its poorly resolved NMR spectrum was indicative of aggregation...
April 20, 2019: Protein Science
Xinmiao Fu, Zengyi Chang
Protein biogenesis and quality control are essential for maintaining a functional pool of proteins and involve numerous protein factors that dynamically and transiently interact with each other and with the substrate proteins in living cells. Conventional methods are hardly effective for studying such dynamic, transient, and weak protein-protein interactions as occur in cells. Herein we review how the site-directed photo-crosslinking approach, which relies on the genetic incorporation of a photo-reactive unnatural amino acid into a protein of interest at selected individual amino acid residue position and the covalent trapping of the interacting proteins upon ultraviolent (UV) irradiation, has become a highly efficient way to explore these aspects of protein contacts in living cells...
April 19, 2019: Protein Science
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