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Unfolding Simulations Reveal the Mechanism of Extreme Unfolding Cooperativity in the Kinetically Stable α-Lytic Protease

Neema L. Salimi, Bosco Ho, David A. Agard, B. Montgomery Pettitt
2010 PLoS Computational Biology  
In order to identify the aLP unfolding pathway and the mechanism for its extreme cooperativity, we performed high temperature molecular dynamics unfolding simulations of both aLP and trypsin.  ...  The prokaryotic serine protease a-lytic protease (aLP) has done just that, as its unfolding is both very slow (t 1/2 ,1 year) and so cooperative that partial unfolding is negligible, providing a functional  ...  Street for critical reading of the manuscript. Author Contributions  ... 
doi:10.1371/journal.pcbi.1000689 pmid:20195497 pmcid:PMC2829044 fatcat:bzzg4s6ad5fxtbibjcai5b4o3u

Designed protein reveals structural determinants of extreme kinetic stability

Aron Broom, S. Martha Ma, Ke Xia, Hitesh Rafalia, Kyle Trainor, Wilfredo Colón, Shachi Gosavi, Elizabeth M. Meiering
2015 Proceedings of the National Academy of Sciences of the United States of America  
The design of stable, functional proteins is difficult. Improved design requires a deeper knowledge of the molecular basis for design outcomes and properties.  ...  We demonstrate that the kinetic stability can be predicted and modeled using absolute contact order (ACO) and long-range order (LRO), as well as coarse-grained simulations; the stability arises from a  ...  Protease resistance of a classic extremely kinetically stable protein, α-lytic protease, has been proposed to originate from its large and highly cooperative unfolding energy barrier resulting in a rigid  ... 
doi:10.1073/pnas.1510748112 pmid:26554002 pmcid:PMC4664365 fatcat:2rbqmlf7e5ef3cmxctnslv7cpi

Structural and Mechanistic Exploration of Acid Resistance: Kinetic Stability Facilitates Evolution of Extremophilic Behavior

Brian A. Kelch, Kyle P. Eagen, F. Pinar Erciyas, Elisabeth L. Humphris, Adam R. Thomason, Shinji Mitsuiki, David A. Agard
2007 Journal of Molecular Biology  
A (NAPase), an acid-resistant, kinetically stable protease, and compared these results with a neutrophilic homolog, α-lytic protease (αLP).  ...  Although NAPase and αLP have the same number of acid-titratable residues, kinetic studies revealed that the height of the unfolding free energy barrier for NAPase is less sensitive to acid than that of  ...  We also thank Dr Corie Ralston at the ALS Beamline 8.2.2 for assistance in data collection. We greatly appreciate Q. Justman and Drs L. Rice, C.  ... 
doi:10.1016/j.jmb.2007.02.032 pmid:17382344 fatcat:r675suv5zreshjnthvnhofp22i

Insights from Bacterial Subtilases into the Mechanisms of Intramolecular Chaperone-Mediated Activation of Furin [chapter]

Ujwal Shinde, Gary Thomas
2011 Msphere  
In this chapter we review what we have learned from the folding and activation of prokaryotic subtilisin, discuss how this has molded our understanding of furin maturation, and foray into the concept of  ...  Prokaryotic subtilisins and eukaryotic proprotein convertases (PCs) are two homologous protease subfamilies that belong to the larger ubiquitous super-family called subtilases.  ...  U.S. is supported by grants from the National Science Foundation (NSF-0746589) and the Oregon Nanoscience and Microtechnologies Institute and G.T. is supported by grant from the National Institutes of  ... 
doi:10.1007/978-1-61779-204-5_4 pmid:21805238 pmcid:PMC4300103 fatcat:oibzngs3tza5fakcyznlqtohfu

Kinetic characterization of the critical step in HIV-1 protease maturation

S. K. Sadiq, F. Noe, G. De Fabritiis
2012 Proceedings of the National Academy of Sciences of the United States of America  
The authors declare no conflict of interest. This article is a PNAS Direct Submission.  ...  The highest regions of error (1.6 kcal/mol) corresponded to poorly sampled regions at the extremities of the conformational landscape ( Fig S6) . Kinetics and mechanism.  ...  An additional water molecule was inserted between the lytic peptide bond and the catalytic dyad, as is expected in the general acid/general base (GA/GB) cleavage mechanism (15) .  ... 
doi:10.1073/pnas.1210983109 pmid:23184967 pmcid:PMC3528573 fatcat:5lc7blm27vafpd6ym3sduntovm

Keep on Moving: Discovering and Perturbing the Conformational Dynamics of Enzymes

Gira Bhabha, Justin T. Biel, James S. Fraser
2014 Accounts of Chemical Research  
Recently identified rescue mutations restore function, but the mechanism by which they do so remains unclear. The exact role of any changes in the dynamics remains an open question.  ...  In DHFR, mutations that alter the ability of the active site to sample productive higher energy states on the millisecond time scale reduce the rate of hydride transfer significantly.  ...  ) of α-lytic protease (upper) is a kinetically trapped structure.  ... 
doi:10.1021/ar5003158 pmid:25539415 pmcid:PMC4334266 fatcat:3crsuthbvzggbbqwimhr7rpzzu

Self-catalyzed growth of S layers via an amorphous-to-crystalline transition limited by folding kinetics

S. Chung, S.-H. Shin, C. R. Bertozzi, J. J. De Yoreo
2010 Proceedings of the National Academy of Sciences of the United States of America  
However, a clear picture of the assembly mechanism, either in vivo or in vitro, has remained elusive due in part to a lack of dynamic structural information (15).  ...  Analysis of the growth kinetics leads to a quantitative model in which tetramer creation is rate limiting.  ...  The authors declare no conflict of interest. This article is a PNAS Direct Submission.  ... 
doi:10.1073/pnas.1008280107 pmid:20823255 pmcid:PMC2944705 fatcat:y2o7btgj5za55bmeko23dv5hfi

The 28th Annual Symposium of The Protein Society: Program & Abstracts

2014 Protein Science  
We have developed a quantitative analysis of the cooperativity of the unfolding process using a 4 parameter sigmoidal equation and use it to demonstrate that ligand interactions lead to changes in unfolding  ...  The mechanism by which AKT alone and in cooperation with c-MYC regulates Pol I transcription remains unknown.  ...  Unfolding of 1O6D is complex in that waiting well beyond five half-lives for equilibration, as judged from kinetic studies, results in shifts in the unfolding and refolding "equilibrium" curves.  ... 
doi:10.1002/pro.2504 pmid:25043257 pmcid:PMC4116645 fatcat:yjhug3aif5futn3icovvrkgebm

Inhibition of the Tumor Necrosis Factor-α-converting Enzyme by Its Pro Domain

Patricia E. Gonzales, Ariel Solomon, Ann B. Miller, M. Anthony Leesnitzer, Irit Sagi, Marcos E. Milla
2004 Journal of Biological Chemistry  
To study the inhibitory properties of the pro domain of TACE, we have expressed it in isolation from the rest of the protease.  ...  The disintegrin/cysteine-rich region in isolation also decreases the interaction of TACE Pro with the catalytic domain.  ...  David Becherer for advice and for generously providing the original TACE clone used for vector construction and Jennifer Leonard for help with vector design and construction and for sharing reagents.  ... 
doi:10.1074/jbc.m401311200 pmid:15100227 fatcat:k5xzxnnxnbbxxmsegm4bozcjk4

13th EBSA congress, July 24–28, 2021, Vienna, Austria

2021 European Biophysics Journal  
EBSA is really grateful to our host colleagues from the Austrian Biophysical Society for accepting the challenge of organizing our Congress in Vienna during these extremely difficult times, despite being  ...  Once more, EBSA is also proud to recognize in 2021, in the context of the Vienna Congress, the achievements of some of our star biophysicists, who have been awarded the two main biannual EBSA Prizes: The  ...  Analysis of these simulations revealed the key interactions and sequence of events involved in the occlusion mechanism. Posters -4.  ... 
doi:10.1007/s00249-021-01558-w pmid:34245338 pmcid:PMC8272448 fatcat:z2svytd4kbamrmvarle4lxwtxm

Obstructing Toxin Pathways by Targeted Pore Blockage

Ekaterina M. Nestorovich, Sergey M. Bezrukov
2012 Chemical Reviews  
In accordance with the mechanism of their action, they are often called the pore-forming toxins (PFT).  ...  A crucial property of many exotoxins is their ability to exist in two states: a stable water-soluble conformation and an integral membrane pore 1 .  ...  On the other hand, the lipid bilayers are mechanically less stable compared to the solid-state nanopores.  ... 
doi:10.1021/cr300141q pmid:23057504 pmcid:PMC3681896 fatcat:xbhhgfduwjaoxmpjdzoyz2gzb4

1 Keynote address by Nobel Laureate Phillip A. Sharp the 21st century opened with a revolution in RNA biology

Phillip A. Sharp
2015 Journal of Biomolecular Structure and Dynamics  
The discoveries of RNA interference and the evolutionary conservation of microRNAs at the turn of the century heralded a revolution in RNA Biology and the development of important innovations.  ...  Long non-coding RNAs regulate the expression of genes through both cis and trans mechanisms and provide organization to the nucleus.  ...  Mechanisms and implications of transcription blockage by guanine-rich DNA sequences. Proceedings of the National Academy of Sciences, 107, 12816-12821. Belotserkovskii, B. P., Mirkin, S.  ... 
doi:10.1080/07391102.2015.1032624 fatcat:w7iil7k3ize77bjkthcyi52ohy

Relationship between Enzyme Specificity and the Backbone Dynamics of Free and Inhibited α-Lytic Protease†,‡

Jonathan H. Davis, David A. Agard
1998 Biochemistry  
To better understand the structural basis for the observed patterns in substrate specificity, the backbone dynamics of R-lytic protease have been investigated using 15 N relaxation measurements.  ...  Slow motions, suggestive of backbone plasticity, are observed in most of the binding pocket residues. This may point to a mechanism for the observed broad specificity of the enzyme.  ...  SUPPORTING INFORMATION AVAILABLE One table of the relaxation rates and NOE values of free and inhibited R-LP and a table of the spectral density values (12 pages).  ... 
doi:10.1021/bi972963p pmid:9601029 fatcat:vlumjwt4dbejzipmnm7z23hgsi


2019 Seibutsu Butsuri  
SH3 domains are marginally stable and exist in equilibrium between folded and unfolded states.  ...  We created a nano-sized space using DNA origami, and examined mechanical unfolding of the GQ and iM in the nanocages using optical tweezers.  ...  In this study, to reveal the detailed mechanism of Ub transfer by full length E6AP E3 ligase, we tried to observe structural dynamics of full length E6AP E3 ligase using HS-AFM. 3Pos189 Kinesin transport  ... 
doi:10.2142/biophys.59.s1 fatcat:rsudhlmaanetrhmdxjgsiyorme

The SARS CoV-2 spike domain, RGD and integrin binding effect-relationship for vaccine design strategy

M Luisetto, G Tarro, Edbey Khaled, N Almukthar, L Cabianca, GR Mashori, Ilman Ahnaf, AR Yesvi, OY Latyschev
2021 Annals of Proteomics and Bioinformatics  
A better understanding in this process can be used to improve safety of the new generation of COVID vaccine.  ...  Spike protein and its domains are involved in producing pathological effect of the COVID-19 disease.  ...  Vallabh Janardhan, et al: "Mechanisms of blood-clots and stroke in COVID-19: In Panel D, a cascade of events unfolds resulting in blood -clots and strokes.  ... 
doi:10.29328/journal.apb.1001014 fatcat:dgzqg4ranzcozamafmskgpdrre
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