scholarly journals Rational Discovery of New Folds for Human Solute Carrier Proteins

2021 ◽  
Author(s):  
Tengyu Xie ◽  
Ximin Chi ◽  
Bangdong Huang ◽  
Fangfei Ye ◽  
Qiang Zhou ◽  
...  
Keyword(s):  
Physiological Function ◽  
Sequence Similarity ◽  
Evolutionary Relationship ◽  
Structural Data ◽  
Working Mechanism ◽  
Solute Carrier ◽  
And Function ◽  
Solute Transporters ◽  
Solute Transporter ◽  
Comprehensive Study

Solute carrier superfamily (SLC) is the largest group responsible for transmembrane transport of substances in human cells. It includes more than 400 members that can be divided into 65 families according to their physiological function and sequence similarity. Different families of solute transporters can adopt the same or different folds that determines the working mechanism and reflects the evolutionary relationship between SLC members. Analysis of structural data shows that there are 13 different folds in the solute carrier superfamily covering 40 families and 342 members. To further study their working mechanism, we systematically explored the SLC superfamily to find more folds. Our results indicate that there are at least three new folds in the solute transporter superfamily among which the SLC44 family is experimentally verified to have a new fold. Our work has laid a foundation and provided important insights for the systematic and comprehensive study on the structure and function of solute carriers.

scholarly journals Structural and functional analysis of the Na+/H+ exchanger

2007 ◽  
Vol 401 (3) ◽  
pp. 623-633 ◽  
Author(s):  
Emily R. Slepkov ◽  
Jan K. Rainey ◽  
Brian D. Sykes ◽  
Larry Fliegel
Keyword(s):  
Intracellular Ph ◽  
Sequence Similarity ◽  
Structural Data ◽  
Structural Similarity ◽  
Integral Membrane Protein ◽  
Volume Control ◽  
Amino Acid Residues ◽  
Physiological Processes ◽  
High Resolution Structure ◽  
Extracellular Sodium

The mammalian NHE (Na+/H+ exchanger) is a ubiquitously expressed integral membrane protein that regulates intracellular pH by removing a proton in exchange for an extracellular sodium ion. Of the nine known isoforms of the mammalian NHEs, the first isoform discovered (NHE1) is the most thoroughly characterized. NHE1 is involved in numerous physiological processes in mammals, including regulation of intracellular pH, cell-volume control, cytoskeletal organization, heart disease and cancer. NHE comprises two domains: an N-terminal membrane domain that functions to transport ions, and a C-terminal cytoplasmic regulatory domain that regulates the activity and mediates cytoskeletal interactions. Although the exact mechanism of transport by NHE1 remains elusive, recent studies have identified amino acid residues that are important for NHE function. In addition, progress has been made regarding the elucidation of the structure of NHEs. Specifically, the structure of a single TM (transmembrane) segment from NHE1 has been solved, and the high-resolution structure of the bacterial Na+/H+ antiporter NhaA has recently been elucidated. In this review we discuss what is known about both functional and structural aspects of NHE1. We relate the known structural data for NHE1 to the NhaA structure, where TM IV of NHE1 shows surprising structural similarity with TM IV of NhaA, despite little primary sequence similarity. Further experiments that will be required to fully understand the mechanism of transport and regulation of the NHE1 protein are discussed.

scholarly journals The proteome: structure, function and evolution

2006 ◽  
Vol 361 (1467) ◽  
pp. 441-451 ◽  
Author(s):  
Keiran Fleming ◽  
Lawrence A Kelley ◽  
Suhail A Islam ◽  
Robert M MacCallum ◽  
Arne Muller ◽  
...  
Keyword(s):  
Protein Function ◽  
Sequence Similarity ◽  
Structural Annotation ◽  
New Approach ◽  
Link Type ◽  
University College London ◽  
Automated Pipeline ◽  
3D Genomics ◽  
And Function ◽  
Structural Homologue

This paper reports two studies to model the inter-relationships between protein sequence, structure and function. First, an automated pipeline to provide a structural annotation of proteomes in the major genomes is described. The results are stored in a database at Imperial College, London (3D-GENOMICS) that can be accessed at www.sbg.bio.ic.ac.uk . Analysis of the assignments to structural superfamilies provides evolutionary insights. 3D-GENOMICS is being integrated with related proteome annotation data at University College London and the European Bioinformatics Institute in a project known as e-protein ( http://www.e-protein.org/ ). The second topic is motivated by the developments in structural genomics projects in which the structure of a protein is determined prior to knowledge of its function. We have developed a new approach PHUNCTIONER that uses the gene ontology (GO) classification to supervise the extraction of the sequence signal responsible for protein function from a structure-based sequence alignment. Using GO we can obtain profiles for a range of specificities described in the ontology. In the region of low sequence similarity (around 15%), our method is more accurate than assignment from the closest structural homologue. The method is also able to identify the specific residues associated with the function of the protein family.

scholarly journals In-silico prediction and observations of nuclear matrix attachment

2006 ◽  
Vol 11 (2) ◽  
Author(s):  
Adrian Platts ◽  
Amelia Quayle ◽  
Stephen Krawetz
Keyword(s):  
Nuclear Matrix ◽  
In Silico ◽  
Sequence Similarity ◽  
Loop Model ◽  
Simple Loop ◽  
Structural Framework ◽  
The Subject ◽  
In Silico Predictions ◽  
The One ◽  
And Function

AbstractThe nuclear matrix is a functionally adaptive structural framework interior to the nuclear envelope. The nature and function of this nuclear organizer remains the subject of widespread discussion in the epigenetic literature. To draw this discussion together with a view to suggest a way forward we summarize the biochemical evidence for the modalities of DNA-matrix binding alongside the in-silico predictions. Concordance is exhibited at various, but not all levels. On the one hand, both the reiteration and sequence similarity of some elements of Matrix Attachment Regions suggest conservation. On the other hand, in-silico predictions suggest additional unique components. In bringing together biological and sequence evidence we conclude that binding may be hierarchical in nature, reflective of a biological role in replicating, transcribing and potentiating chromatin. Nuclear matrix binding may well be more complex than the widely accepted simple loop model.

Abstract 231: Uncovering the Mechanism and Function of Newly Discovered KCNQ1-Transporter Complexes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Daniel L Neverisky ◽  
Geoffrey W Abbott
Keyword(s):  
Complex Formation ◽  
Cardiac Function ◽  
Glucose Transporter ◽  
Beta Subunits ◽  
Lone Atrial Fibrillation ◽  
Potassium Efflux ◽  
Regulatory Subunits ◽  
And Function ◽  
Solute Transporters ◽  
Normal Cardiac Function

The KCNQ1 voltage-gated potassium channel is essential for human ventricular repolarization, permitting potassium efflux from excited cardiomyocytes to end each action potential and repolarize the heart. In cardiomyocytes, KCNQ1 is modulated by interaction with beta-subunits from the KCNE gene family, each of which significantly alters KCNQ1 channel function. KCNQ1 mutations are the most common identified genetic basis for Long QT syndrome (LQTS) and are also associated with lone atrial fibrillation (AF). The sodium-dependent myo-inositol transporter 1 (SMIT1) mediates cellular uptake of myo-inositol, an essential osmolyte that also represents an important substrate for phosphatidylinositol signaling pathways that regulate a plethora of ion channels including those essential for human cardiac function. We recently discovered that KCNQ1 can form heteromeric, co-regulatory complexes with Na+-coupled solute transporters including SMIT1, SMIT2 and glucose transporter SGLT1. These findings represent the first reported example of formation of an ion channel-solute transporter complex. Having discovered KCNQ1-SMIT1 complexes in mouse choroid plexus epithelium, we are currently investigating whether these types of complexes occur in the heart, how their function is altered by the various cardiac-expressed KCNE regulatory subunits or by arrhythmia-associated mutations, and which parts of KCNQ1 coordinate complex formation. Here, we present evidence of KCNQ1-SMIT1 co-assembly in pig heart based on co-immunoprecipitation experiments. Using KCNQ1-KCNQ4 chimeras we also begin to define which specific regions of KCNQ1 are required for complex formation with SMIT1. Finally, we present data showing the effects of SMIT1 on complexes formed by KCNQ1 and KCNE1, 2 and 3. KCNQ1-transporter complexes provide a potential hub for electrochemical crosstalk in normal cardiac function and in arrhythmogenesis.

scholarly journals Ambidextrous helical nanotubes from self-assembly of designed helical hairpin motifs

2019 ◽  
Vol 116 (29) ◽  
pp. 14456-14464 ◽  
Author(s):  
Spencer A. Hughes ◽  
Fengbin Wang ◽  
Shengyuan Wang ◽  
Mark A. B. Kreutzberger ◽  
Tomasz Osinski ◽  
...  
Keyword(s):  
Tandem Repeat ◽  
Self Assembly ◽  
Sequence Similarity ◽  
Structural Data ◽  
Consensus Sequences ◽  
Repeat Proteins ◽  
Helical Hairpin ◽  
Tandem Repeat Proteins ◽  
Helical Protein ◽  
Helical Geometry

Tandem repeat proteins exhibit native designability and represent potentially useful scaffolds for the construction of synthetic biomimetic assemblies. We have designed 2 synthetic peptides, HEAT_R1 and LRV_M3Δ1, based on the consensus sequences of single repeats of thermophilic HEAT (PBS_HEAT) and Leucine-Rich Variant (LRV) structural motifs, respectively. Self-assembly of the peptides afforded high-aspect ratio helical nanotubes. Cryo-electron microscopy with direct electron detection was employed to analyze the structures of the solvated filaments. The 3D reconstructions from the cryo-EM maps led to atomic models for the HEAT_R1 and LRV_M3Δ1 filaments at resolutions of 6.0 and 4.4 Å, respectively. Surprisingly, despite sequence similarity at the lateral packing interface, HEAT_R1 and LRV_M3Δ1 filaments adopt the opposite helical hand and differ significantly in helical geometry, while retaining a local conformation similar to previously characterized repeat proteins of the same class. The differences in the 2 filaments could be rationalized on the basis of differences in cohesive interactions at the lateral and axial interfaces. These structural data reinforce previous observations regarding the structural plasticity of helical protein assemblies and the need for high-resolution structural analysis. Despite these observations, the native designability of tandem repeat proteins offers the opportunity to engineer novel helical nanotubes. Moreover, the resultant nanotubes have independently addressable and chemically distinguishable interior and exterior surfaces that would facilitate applications in selective recognition, transport, and release.

Long-term Memory Upscales Volume of Postsynaptic Densities in the Process that Requires Autophosphorylation of αCaMKII

2019 ◽  
Vol 30 (4) ◽  
pp. 2573-2585 ◽  
Author(s):  
Małgorzata Alicja Śliwińska ◽  
Anna Cały ◽  
Malgorzata Borczyk ◽  
Magdalena Ziółkowska ◽  
Edyta Skonieczna ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Smooth Endoplasmic Reticulum ◽  
Structural Data ◽  
Long Term Memory ◽  
Brain Circuits ◽  
Hippocampal Area ◽  
And Function ◽  
And Storage ◽  
Old Mice

Abstract It is generally accepted that formation and storage of memory relies on alterations of the structure and function of brain circuits. However, the structural data, which show learning-induced and long-lasting remodeling of synapses, are still very sparse. Here, we reconstruct 1927 dendritic spines and their postsynaptic densities (PSDs), representing a postsynaptic part of the glutamatergic synapse, in the hippocampal area CA1 of the mice that underwent spatial training. We observe that in young adult (5 months), mice volume of PSDs, but not the volume of the spines, is increased 26 h after the training. The training-induced growth of PSDs is specific for the dendritic spines that lack smooth endoplasmic reticulum and spine apparatuses, and requires autophosphorylation of αCaMKII. Interestingly, aging alters training-induced ultrastructural remodeling of dendritic spines. In old mice, both the median volumes of dendritic spines and PSDs shift after training toward bigger values. Overall, our data support the hypothesis that formation of memory leaves long-lasting footprint on the ultrastructure of brain circuits; however, the form of circuit remodeling changes with age.

scholarly journals N-Linked Glycosylation Modulates Golgi-Independent Vacuolar Sorting Mediated by the Plant Specific Insert

Plants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 312 ◽  
Author(s):  
Vanessa Vieira ◽  
Bruno Peixoto ◽  
Mónica Costa ◽  
Susana Pereira ◽  
José Pissarra ◽  
...  
Keyword(s):  
Sequence Similarity ◽  
Site Directed Mutagenesis ◽  
Research Gaps ◽  
Glycosylation Pattern ◽  
High Sequence Similarity ◽  
Post Translational Modifications ◽  
Vacuolar Sorting ◽  
Prevacuolar Compartment ◽  
Cardosin A ◽  
Comprehensive Study

In plant cells, the conventional route to the vacuole involves the endoplasmic reticulum, the Golgi and the prevacuolar compartment. However, over the years, unconventional sorting to the vacuole, bypassing the Golgi, has been described, which is the case of the Plant-Specific Insert (PSI) of the aspartic proteinase cardosin A. Interestingly, this Golgi-bypass ability is not a characteristic shared by all PSIs, since two related PSIs showed to have different sensitivity to ER-to-Golgi blockage. Given the high sequence similarity between the PSI domains, we sought to depict the differences in terms of post-translational modifications. In fact, one feature that draws our attention is that one is N-glycosylated and the other one is not. Using site-directed mutagenesis to obtain mutated versions of the two PSIs, with and without the glycosylation motif, we observed that altering the glycosylation pattern interferes with the trafficking of the protein as the non-glycosylated PSI-B, unlike its native glycosylated form, is able to bypass ER-to-Golgi blockage and accumulate in the vacuole. This is also true when the PSI domain is analyzed in the context of the full-length cardosin. Regardless of opening exciting research gaps, the results obtained so far need a more comprehensive study of the mechanisms behind this unconventional direct sorting to the vacuole.

scholarly journals Molecular Characterisation of a Novel and Highly Divergent Passerine Adenovirus 1

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 1036
Author(s):  
Ajani Athukorala ◽  
Jade K. Forwood ◽  
David N. Phalen ◽  
Subir Sarker
Keyword(s):  
Complete Genome ◽  
Sequence Similarity ◽  
Evolutionary Relationship ◽  
Passerine Bird ◽  
The Novel ◽  
Transmembrane Helices ◽  
Novel Genes ◽  
Separate Species ◽  
Natural Host Species ◽  
Genes Encoding

Wild birds harbour a large number of adenoviruses that remain uncharacterised with respect to their genomic organisation, diversity, and evolution within complex ecosystems. Here, we present the first complete genome sequence of an atadenovirus from a passerine bird that is tentatively named Passerine adenovirus 1 (PaAdV-1). The PaAdV-1 genome is 39,664 bp in length, which was the longest atadenovirus to be sequenced, to the best of our knowledge, and contained 42 putative genes. Its genome organisation was characteristic of the members of genus Atadenovirus; however, the novel PaAdV-1 genome was highly divergent and showed the highest sequence similarity with psittacine adenovirus-3 (55.58%). Importantly, PaAdV-1 complete genome was deemed to contain 17 predicted novel genes that were not present in any other adenoviruses sequenced to date, with several of these predicted novel genes encoding proteins that harbour transmembrane helices. Subsequent analysis of the novel PaAdV-1 genome positioned phylogenetically to a distinct sub-clade with all others sequenced atadenoviruses and did not show any obvious close evolutionary relationship. This study concluded that the PaAdV-1 complete genome described here is not closely related to any other adenovirus isolated from avian or other natural host species and that it should be considered a separate species.

scholarly journals Insight into the Contribution and Disruption of Host Processes during HDV Replication

Viruses ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 21 ◽  
Author(s):  
Gabrielle Goodrum ◽  
Martin Pelchat
Keyword(s):  
Rna Virus ◽  
Sequence Similarity ◽  
Evolutionary Relationship ◽  
Circular Rna ◽  
Helper Virus ◽  
Protein Coding ◽  
Subviral Rnas ◽  
B Virus ◽  
Infected Cells ◽  
Limited Protein

Hepatitis delta virus (HDV) is unique among animal viruses. HDV is a satellite virus of the hepatitis B virus (HBV), however it shares no sequence similarity with its helper virus and replicates independently in infected cells. HDV is the smallest human pathogenic RNA virus and shares numerous characteristics with viroids. Like viroids, HDV has a circular RNA genome which adopts a rod-like secondary structure, possesses ribozyme domains, replicates in the nucleus of infected cells by redirecting host DNA-dependent RNA polymerases (RNAP), and relies heavily on host proteins for its replication due to its small size and limited protein coding capacity. These similarities suggest an evolutionary relationship between HDV and viroids, and information on HDV could allow a better understanding of viroids and might globally help understanding the pathogenesis and molecular biology of these subviral RNAs. In this review, we discuss the host involvement in HDV replication and its implication for HDV pathogenesis.

scholarly journals Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

2017 ◽  
Vol 58 (1) ◽  
pp. R1-R13 ◽  
Author(s):  
Gillian A Gray ◽  
Christopher I White ◽  
Raphael F P Castellan ◽  
Sara J McSweeney ◽  
Karen E Chapman
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Systemic Corticosteroid ◽  
Physiological Function ◽  
Pressure Overload ◽  
Hydroxysteroid Dehydrogenase ◽  
And Function ◽  
Glucocorticoid Metabolism

Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.

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