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1621. A Whole-Body Model for Glycogen Regulation Reveals a Critical Role for Substrate Cycling in Maintaining Blood Glucose Homeostasis

Title Tesim:
A Whole-Body Model for Glycogen Regulation Reveals a Critical Role for Substrate Cycling in Maintaining Blood Glucose Homeostasis
Creator:
Elston, Timothy C., Todd Gehris, Abby, Morgan, Kevin T., Gomez, Shawn M., and Xu, Ke
Date of publication:
2011
Abstract Tesim:
Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active) and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile) cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into “whole-body” contextual models that mimic in vivo conditions.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/kbtj-ta50
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pcbi.1002272, PMCID: PMC3233304, PMID: 22163177, and Onescience id: c57440567dbed0e2cac5787e70cf584360af2987
ISSN:
1553-734X and 1553-7358
Journal Issue:
12
Journal Title:
PLoS Computational Biology
Journal Volume:
7
Keyword:
Blood Glucose, Liver Glycogen, Glycogen Synthase, Glycogen Phosphorylase, Computer Simulation, Substrate Cycling, and Homeostasis
Language Label:
English
Page Start:
e1002272
Person:
Elston, Timothy C., Todd Gehris, Abby, Morgan, Kevin T., Gomez, Shawn M., and Xu, Ke
Rights Statement Label:
In Copyright
Source:
t435gn11z

1622. Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences

Title Tesim:
Polyglutamine Induced Misfolding of Huntingtin Exon1 is Modulated by the Flanking Sequences
Creator:
Lakhani, Vinal V., Dokholyan, Nikolay V., and Ding, Feng
Date of publication:
2010
Abstract Tesim:
Polyglutamine (polyQ) expansion in exon1 (XN1) of the huntingtin protein is linked to Huntington's disease. When the number of glutamines exceeds a threshold of approximately 36–40 repeats, XN1 can readily form amyloid aggregates similar to those associated with disease. Many experiments suggest that misfolding of monomeric XN1 plays an important role in the length-dependent aggregation. Elucidating the misfolding of a XN1 monomer can help determine the molecular mechanism of XN1 aggregation and potentially help develop strategies to inhibit XN1 aggregation. The flanking sequences surrounding the polyQ region can play a critical role in determining the structural rearrangement and aggregation mechanism of XN1. Few experiments have studied XN1 in its entirety, with all flanking regions. To obtain structural insights into the misfolding of XN1 toward amyloid aggregation, we perform molecular dynamics simulations on monomeric XN1 with full flanking regions, a variant missing the polyproline regions, which are hypothesized to prevent aggregation, and an isolated polyQ peptide (Qn). For each of these three constructs, we study glutamine repeat lengths of 23, 36, 40 and 47. We find that polyQ peptides have a positive correlation between their probability to form a β-rich misfolded state and their expansion length. We also find that the flanking regions of XN1 affect its probability to^x_page_count=28 form a β-rich state compared to the isolated polyQ. Particularly, the polyproline regions form polyproline type II helices and decrease the probability of the polyQ region to form a β-rich state. Additionally, by lengthening polyQ, the first N-terminal 17 residues are more likely to adopt a β-sheet conformation rather than an α-helix conformation. Therefore, our molecular dynamics study provides a structural insight of XN1 misfolding and elucidates the possible role of the flanking sequences in XN1 aggregation.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/vy2n-zx56
Identifier:
Onescience id: cb78db1835e3ba24355b7bd8008d9bb7aa9fae6d, PMID: 20442863, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000772, and PMCID: PMC2861695
ISSN:
1553-7358 and 1553-734X
Journal Issue:
4
Journal Title:
PLoS Computational Biology
Journal Volume:
6
Keyword:
Thermodynamics, Cluster Analysis, Protein Multimerization, Nuclear Proteins, Amino Acid Sequence, Huntington Disease, Molecular Sequence Data, HTT protein, human, Protein Folding, Nerve Tissue Proteins, Protein Structure, Secondary, Exons, Huntingtin Protein, Peptides, and Molecular Dynamics Simulation
Language Label:
English
Page Start:
e1000772
Person:
Lakhani, Vinal V., Dokholyan, Nikolay V., and Ding, Feng
Rights Statement Label:
In Copyright
Source:
hx11xp36s

1623. Genetic Signatures in the Envelope Glycoproteins of HIV-1 that Associate with Broadly Neutralizing Antibodies

Title Tesim:
Genetic Signatures in the Envelope Glycoproteins of HIV-1 that Associate with Broadly Neutralizing Antibodies
Creator:
Greene, Kelli, Daniels, Marcus G., Gao, Feng, Bhattacharya, Tanmoy, Kumar, Amit, Sethi, Anurag, Shaw, George M., Tang, Haili, Li, Ming, Montefiori, David C., Lapedes, Alan S., Korber, Bette, Gnanakaran, S., Seaman, Michael S., Cohen, Myron S., Gao, Hongmei, and Haynes, Barton F.
Date of publication:
2010
Abstract Tesim:
A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/py3f-pj09
Identifier:
PMCID: PMC2951345, Onescience id: 521dc7b516daac28ac9e2f997e7d9d9fa9f3315c, PMID: 20949103, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000955
ISSN:
1553-734X and 1553-7358
Journal Issue:
10
Journal Title:
PLoS Computational Biology
Journal Volume:
6
Keyword:
T-Lymphocyte, Molecular, Logistic Models, Artificial Intelligence, Epitope Mapping, Epitopes, Computational Biology, Mutation, Cluster Analysis, Journal Article, Algorithms, HIV-1, HIV Envelope Protein gp120, Phylogeny, Models, Amino Acid Sequence, Neutralization Tests, DNA Mutational Analysis, Antibodies, Humans, Neutralizing, Sequence Alignment, and HIV Envelope Protein gp41
Language Label:
English
Page Start:
e1000955
Person:
Greene, Kelli, Daniels, Marcus G., Gao, Feng, Bhattacharya, Tanmoy, Kumar, Amit, Sethi, Anurag, Shaw, George M., Tang, Haili, Li, Ming, Montefiori, David C., Lapedes, Alan S., Korber, Bette, Gnanakaran, S., Seaman, Michael S., Cohen, Myron S., Gao, Hongmei, and Haynes, Barton F.
Rights Statement Label:
In Copyright
Source:
rf55zg601

1624. Evolution of a Signaling Nexus Constrained by Protein Interfaces and Conformational States

Title Tesim:
Evolution of a Signaling Nexus Constrained by Protein Interfaces and Conformational States
Creator:
Temple, Brenda R. S., Jones, Corbin D., and Jones, Alan M.
Date of publication:
2010
Abstract Tesim:
Heterotrimeric G proteins act as the physical nexus between numerous receptors that respond to extracellular signals and proteins that drive the cytoplasmic response. The Gα subunit of the G protein, in particular, is highly constrained due to its many interactions with proteins that control or react to its conformational state. Various organisms contain differing sets of Gα-interacting proteins, clearly indicating that shifts in sequence and associated Gα functionality were acquired over time. These numerous interactions constrained much of Gα evolution; yet Gα has diversified, through poorly understood processes, into several functionally specialized classes, each with a unique set of interacting proteins. Applying a synthetic sequence-based approach to mammalian Gα subunits, we established a set of seventy-five evolutionarily important class-distinctive residues, sites where a single Gα class is differentiated from the three other classes. We tested the hypothesis that shifts at these sites are important for class-specific functionality. Importantly, we mapped known and well-studied class-specific functionalities from all four mammalian classes to sixteen of our class-distinctive sites, validating the hypothesis. Our results show how unique functionality can evolve through the recruitment of residues that were ancestrally functional. We also studied acquisition of functionalities by following these evolutionarily important sites in non-mammalian organisms. Our results suggest that many class-distinctive sites were established early on in eukaryotic diversification and were critical for the establishment of new Gα classes, whereas others arose in punctuated bursts throughout metazoan evolution. These Gα class-distinctive residues are rational targets for future structural and functional studies.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/bt11-sh47
Identifier:
Onescience id: e475817dc1ea80ee14b4c19fcfac02fd05e4a7f4, PMID: 20976244, PMCID: PMC2954821, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000962
ISSN:
1553-734X and 1553-7358
Journal Issue:
10
Journal Title:
PLoS Computational Biology
Journal Volume:
6
Keyword:
Protein Interaction Domains and Motifs, Information Theory, Eukaryota, Protein Interaction Mapping, Evolution, Molecular, Animals, Models, Molecular, GTP-Binding Protein beta Subunits, Molecular Sequence Annotation, Phylogeny, Amino Acid Sequence, Molecular Sequence Data, Models, Genetic, Databases, Protein, GTP-Binding Protein alpha Subunits, Adenylyl Cyclases, and Humans
Language Label:
English
Page Start:
e1000962
Person:
Temple, Brenda R. S., Jones, Corbin D., and Jones, Alan M.
Rights Statement Label:
In Copyright
Source:
3f462d55n

1625. Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR

Title Tesim:
Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR
Creator:
Krasowski, Matthew D., Redinbo, Matthew R., Kortagere, Sandhya, Reschly, Erica J., Lill, Markus A., Iyer, Manisha, and Ekins, Sean
Date of publication:
2009
Abstract Tesim:
Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5α-androstan-3β-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/d5ts-xm28
Identifier:
Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000594, PMID: 20011107, Onescience id: bea5435a8f31f4a2d64c01f196bb0447f2cda372, and PMCID: PMC2781111
ISSN:
1553-7358 and 1553-734X
Journal Issue:
12
Journal Title:
PLoS Computational Biology
Journal Volume:
5
Keyword:
Ligands, agonists, Humans, Molecular, Steroid:, Protein, Quantitative, Computational, Crystallography, Models, metabolism, Tertiary, chemistry, Steroid, Receptors, Structure-Activity, Relationship, Biology, Structure, and X-Ray
Language Label:
English
Page Start:
e1000594
Person:
Krasowski, Matthew D., Redinbo, Matthew R., Kortagere, Sandhya, Reschly, Erica J., Lill, Markus A., Iyer, Manisha, and Ekins, Sean
Rights Statement Label:
In Copyright
Source:
vm40z085n

1626. A Structural Model of the Pore-Forming Region of the Skeletal Muscle Ryanodine Receptor (RyR1)

Title Tesim:
A Structural Model of the Pore-Forming Region of the Skeletal Muscle Ryanodine Receptor (RyR1)
Creator:
Dokholyan, Nikolay V., Ramachandran, Srinivas, Meissner, Gerhard, Xu, Le, and Serohijos, Adrian W. R.
Date of publication:
2009
Abstract Tesim:
Ryanodine receptors (RyRs) are ion channels that regulate muscle contraction by releasing calcium ions from intracellular stores into the cytoplasm. Mutations in skeletal muscle RyR (RyR1) give rise to congenital diseases such as central core disease. The absence of high-resolution structures of RyR1 has limited our understanding of channel function and disease mechanisms at the molecular level. Here, we report a structural model of the pore-forming region of RyR1. Molecular dynamics simulations show high ion binding to putative pore residues D4899, E4900, D4938, and D4945, which are experimentally known to be critical for channel conductance and selectivity. We also observe preferential localization of Ca2+ over K+ in the selectivity filter of RyR1. Simulations of RyR1-D4899Q mutant show a loss of preference to Ca2+ in the selectivity filter as seen experimentally. Electrophysiological experiments on a central core disease mutant, RyR1-G4898R, show constitutively open channels that conduct K+ but not Ca2+. Our simulations with G4898R likewise show a decrease in the preference of Ca2+ over K+ in the selectivity filter. Together, the computational and experimental results shed light on ion conductance and selectivity of RyR1 at an atomistic level.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/2pe9-4h32
Identifier:
PMID: 19390614, PMCID: PMC2668181, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000367, and Onescience id: 26e05aba63ded24a7211f9c43b7df35e2d944593
ISSN:
1553-7358 and 1553-734X
Journal Issue:
4
Journal Title:
PLoS Computational Biology
Journal Volume:
5
Keyword:
Molecular dynamics, Biochemical simulations, Intracellular receptors, Single channel recording, Simulation and modeling, Electron cryo-microscopy, Sequence motif analysis, and Ion channels
Language Label:
English
Page Start:
e1000367
Person:
Dokholyan, Nikolay V., Ramachandran, Srinivas, Meissner, Gerhard, Xu, Le, and Serohijos, Adrian W. R.
Rights Statement Label:
In Copyright
Source:
pc289r812

1627. Identification and Rational Redesign of Peptide Ligands to CRIP1, A Novel Biomarker for Cancers

Title Tesim:
Identification and Rational Redesign of Peptide Ligands to CRIP1, A Novel Biomarker for Cancers
Creator:
Wang, Zuncai, Serohijos, Adrian W. R., Tassone, Gina, Dokholyan, Nikolay V., Hao, Jihua, Newton, Gail, Sgroi, Dennis C., and Basilion, James P.
Date of publication:
2008
Abstract Tesim:
Cysteine-rich intestinal protein 1 (CRIP1) has been identified as a novel marker for early detection of cancers. Here we report on the use of phage display in combination with molecular modeling to identify a high-affinity ligand for CRIP1. Panning experiments using a circularized C7C phage library yielded several consensus sequences with modest binding affinities to purified CRIP1. Two sequence motifs, A1 and B5, having the highest affinities for CRIP1, were chosen for further study. With peptide structure information and the NMR structure of CRIP1, the higher-affinity A1 peptide was computationally redesigned, yielding a novel peptide, A1M, whose affinity was predicted to be much improved. Synthesis of the peptide and saturation and competitive binding studies demonstrated approximately a 10–28-fold improvement in the affinity of A1M compared to that of either A1 or B5 peptide. These techniques have broad application to the design of novel ligand peptides.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/vmr7-2w77
Identifier:
PMID: 18670594, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000138, PMCID: PMC2453235, and Onescience id: 323f7b1b378e5449f2bf0b71696e15ecbf874d1e
ISSN:
1553-734X and 1553-7358
Journal Issue:
8
Journal Title:
PLoS Computational Biology
Journal Volume:
4
Keyword:
Humans, Coliphages, CRIP1 protein, human, Models, Molecular, Thermodynamics, Amino Acid Motifs, Binding, Competitive, Peptides, Protein Binding, Ligands, Carrier Proteins, Computational Biology, Peptide Library, and LIM Domain Proteins
Language Label:
English
Page Start:
e1000138
Person:
Wang, Zuncai, Serohijos, Adrian W. R., Tassone, Gina, Dokholyan, Nikolay V., Hao, Jihua, Newton, Gail, Sgroi, Dennis C., and Basilion, James P.
Rights Statement Label:
In Copyright
Source:
dj52wd18q

1628. Dose-to-Duration Encoding and Signaling beyond Saturation in Intracellular Signaling Networks

Title Tesim:
Dose-to-Duration Encoding and Signaling beyond Saturation in Intracellular Signaling Networks
Creator:
Dohlman, Henrik G., Elston, Timothy C., Hao, Nan, and Behar, Marcelo
Date of publication:
2008
Abstract Tesim:
The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this “dose-to-duration” conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of “signaling beyond saturation” in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/y02b-a942
Identifier:
Onescience id: ecb012e057f8bd7297666cfcaff789acc27a080e, PMCID: PMC2543107, PMID: 18846202, and Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000197
ISSN:
1553-734X and 1553-7358
Journal Issue:
10
Journal Title:
PLoS Computational Biology
Journal Volume:
4
Keyword:
Pheromones, Feedback, Physiological, Time Factors, Signal Transduction, Models, Biological, Receptors, Cell Surface, Saccharomyces cerevisiae Proteins, Computational Biology, Saccharomyces cerevisiae, Receptors, Pheromone, and Dose-Response Relationship, Drug
Language Label:
English
Page Start:
e1000197
Person:
Dohlman, Henrik G., Elston, Timothy C., Hao, Nan, and Behar, Marcelo
Rights Statement Label:
In Copyright
Source:
6395wg13g

1629. Active Nuclear Receptors Exhibit Highly Correlated AF-2 Domain Motions

Title Tesim:
Active Nuclear Receptors Exhibit Highly Correlated AF-2 Domain Motions
Creator:
Temple, Brenda R. S., Dokholyan, Nikolay V., Redinbo, Matthew R., Teotico, Denise G., Frazier, Monica L., and Ding, Feng
Date of publication:
2008
Abstract Tesim:
Nuclear receptor ligand binding domains (LBDs) convert ligand binding events into changes in gene expression by recruiting transcriptional coregulators to a conserved activation function-2 (AF-2) surface. While most nuclear receptor LBDs form homo- or heterodimers, the human nuclear receptor pregnane X receptor (PXR) forms a unique and essential homodimer and is proposed to assemble into a functional heterotetramer with the retinoid X receptor (RXR). How the homodimer interface, which is located 30 Å from the AF-2, would affect function at this critical surface has remained unclear. By using 20- to 30-ns molecular dynamics simulations on PXR in various oligomerization states, we observed a remarkably high degree of correlated motion in the PXR–RXR heterotetramer, most notably in the four helices that create the AF-2 domain. The function of such correlation may be to create “active-capable” receptor complexes that are ready to bind to transcriptional coactivators. Indeed, we found in additional simulations that active-capable receptor complexes involving other orphan or steroid nuclear receptors also exhibit highly correlated AF-2 domain motions. We further propose a mechanism for the transmission of long-range motions through the nuclear receptor LBD to the AF-2 surface. Taken together, our findings indicate that long-range motions within the LBD scaffold are critical to nuclear receptor function by promoting a mobile AF-2 state ready to bind coactivators.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/apnx-y011
Identifier:
PMID: 18617990, Publisher DOI: https://doi.org/10.1371/journal.pcbi.1000111, Onescience id: 7d03acf279fc61581b78cf1547ce9f0497cb180f, and PMCID: PMC2432469
ISSN:
1553-734X and 1553-7358
Journal Issue:
7
Journal Title:
PLoS Computational Biology
Journal Volume:
4
Keyword:
Receptors, Cytoplasmic and Nuclear, Energy Transfer, Dimerization, Amino Acid Sequence, Models, Molecular, Retinoid X Receptors, Motion, Protein Binding, Nuclear Proteins, Humans, Binding Sites, Receptors, Steroid, Protein Interaction Domains and Motifs, and Conserved Sequence
Language Label:
English
Page Start:
e1000111
Person:
Temple, Brenda R. S., Dokholyan, Nikolay V., Redinbo, Matthew R., Teotico, Denise G., Frazier, Monica L., and Ding, Feng
Rights Statement Label:
In Copyright
Source:
nv9359950

1630. Correction: Emergence of Protein Fold Families through Rational Design

Title Tesim:
Correction: Emergence of Protein Fold Families through Rational Design
Creator:
Ding, Feng and Dokholyan, Nikolay V.
Date of publication:
2006
Abstract Tesim:
Diverse proteins with similar structures are grouped into families of homologs and analogs, if their sequence similarity is higher or lower, respectively, than 20%–30%. It was suggested that protein homologs and analogs originate from a common ancestor and diverge in their distinct evolutionary time scales, emerging as a consequence of the physical properties of the protein sequence space. Although a number of studies have determined key signatures of protein family organization, the sequence-structure factors that differentiate the two evolution-related protein families remain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologous families, lead to distinct packing of the protein core and, thus, novel compositions of core residues. The latter process leads to the formation of distinct families of homologs. We propose that such differentiation results in the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa, to computationally design protein sequences that correspond to the same fold family. We find that analogous proteins emerge when a backbone structure deviates only 1–2 Å root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to ~25%–30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences, thereby validating our computational design methodology.
Resource type:
Article
Deposit Record:
http://windsor.libint.unc.edu:8181/fcrepo/rest/prod/f8/ca/d5/63/f8cad563-9b67-4053-a6f6-f544764d92b7
Type:
http://purl.org/dc/dcmitype/Text
DOI:
https://doi.org/10.17615/v907-at60
Identifier:
Onescience id: 8c89cf086347e6f30ab1ea4ae1990cd42e0e4f30, PMID: 16839198, Publisher DOI: https://doi.org/10.1371/journal.pcbi.0020085, and PMCID: PMC1487181
ISSN:
1553-734X and 1553-7358
Journal Issue:
7
Journal Title:
PLoS Computational Biology
Journal Volume:
2
Keyword:
Computational Biology, Protein Conformation, Software, Protein Structure, Tertiary, Models, Molecular, Entropy, Computers, Proteins, Escherichia coli, Evolution, Molecular, Stochastic Processes, Protein Folding, and Molecular Conformation
Language Label:
English
Page Start:
e85
Person:
Ding, Feng and Dokholyan, Nikolay V.
Rights Statement Label:
In Copyright
Source:
cv43p449n