scholarly journals Repeat protein engineering: creating functional nanostructures/biomaterials from modular building blocks

2013 ◽  
Vol 41 (5) ◽  
pp. 1152-1158 ◽  
Author(s):  
Ewan R.G. Main ◽  
Jonathan J. Phillips ◽  
Charlotte Millership
Keyword(s):  
Protein Interactions ◽  
Self Assembly ◽  
Building Blocks ◽  
Simple Relationship ◽  
Stimuli Responsive ◽  
Protein Protein Interactions ◽  
Sequence Structure ◽  
Diverse Range ◽  
Repeat Proteins ◽  
And Function

There is enormous interest in molecular self-assembly and the development of biological systems to form smart nanostructures for biotechnology (so-called ‘bottom-up fabrications’). Repeat proteins are ideal choices for development of such systems as they: (i) possess a relatively simple relationship between sequence, structure and function; (ii) are modular and non-globular in structure; (iii) act as diverse scaffolds for the mediation of a diverse range of protein–protein interactions; and (iv) have been extensively studied and successfully engineered and designed. In the present review, we summarize recent advances in the use of engineered repeat proteins in the self-assembly of novel materials, nanostructures and biosensors. In particular, we show that repeat proteins are excellent monomeric programmable building blocks that can be triggered to associate into a range of morphologies and can readily be engineered as stimuli-responsive biofunctional materials.

Targeting Kinase Interaction Networks: A New Paradigm in PPI Based Design of Kinase Inhibitors

2019 ◽  
Vol 19 (6) ◽  
pp. 467-485 ◽  
Author(s):  
Pranitha Jenardhanan ◽  
Manivel Panneerselvam ◽  
Premendu P. Mathur
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Disease Onset ◽  
Peptide Inhibitors ◽  
Protein Protein Interactions ◽  
New Paradigm ◽  
Diverse Range ◽  
Protein Protein Interaction ◽  
Domain Specific ◽  
And Function

Background: Kinases are key modulators in regulating diverse range of cellular activities and are an essential part of the protein-protein interactome. Understanding the interaction of kinases with different substrates and other proteins is vital to decode the cell signaling machinery as well as causative mechanism for disease onset and progression. Objective: The objective of this review is to present all studies on the structure and function of few important kinases and highlight the protein-protein interaction (PPI) mechanism of kinases and the kinase specific interactome databases and how such studies could be utilized to develop anticancer drugs. Methods: The article is a review of the detailed description of the various domains in kinases that are involved in protein-protein interactions and specific inhibitors developed targeting these PPI domains. Results: The review has surfaced in depth the interacting domains in key kinases and their features and the roles of PPI in the human kinome and the various signaling cascades that are involved in certain types of cancer. Conclusion: The insight availed into the mechanism of existing peptide inhibitors and peptidomimetics against kinases will pave way for the design and generation of domain specific peptide inhibitors with better productivity and efficiency and the various software and servers available can be of great use for the identification and analysis of protein-protein interactions.

scholarly journals Transactivation Functions of the N-Terminal Domains of Nuclear Hormone Receptors: Protein Folding and Coactivator Interactions

2003 ◽  
Vol 17 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Raj Kumar ◽  
E. Brad Thompson
Keyword(s):  
Dna Binding ◽  
Protein Interactions ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Protein Protein Interactions ◽  
Carboxy Terminal ◽  
And Function ◽  
Terminal Domains

Abstract The N-terminal domains (NTDs) of many members of the nuclear hormone receptor (NHR) family contain potent transcription-activating functions (AFs). Knowledge of the mechanisms of action of the NTD AFs has lagged, compared with that concerning other important domains of the NHRs. In part, this is because the NTD AFs appear to be unfolded when expressed as recombinant proteins. Recent studies have begun to shed light on the structure and function of the NTD AFs. Recombinant NTD AFs can be made to fold by application of certain osmolytes or when expressed in conjunction with a DNA-binding domain by binding that DNA-binding domain to a DNA response element. The sequence of the DNA binding site may affect the functional state of the AFs domain. If properly folded, NTD AFs can bind certain cofactors and primary transcription factors. Through these, and/or by direct interactions, the NTD AFs may interact with the AF2 domain in the ligand binding, carboxy-terminal portion of the NHRs. We propose models for the folding of the NTD AFs and their protein-protein interactions.

A Dynamic Route to Structure and Function: Recent Advances in Imine-Based Organic Nanostructured Materials

2013 ◽  
Vol 66 (1) ◽  
pp. 9 ◽  
Author(s):  
Yi Liu ◽  
Zhan-Ting Li
Keyword(s):  
Self Assembly ◽  
Reaction System ◽  
Functional Materials ◽  
Building Blocks ◽  
The Self ◽  
Interlocked Molecules ◽  
Functional Aspects ◽  
Imine Bond ◽  
And Function ◽  
Dynamic Route

The chemistry of imine bond formation from simple aldehyde and amine precursors is among the most powerful dynamic covalent chemistries employed for the construction of discrete molecular objects and extended molecular frameworks. The reversible nature of the C=N bond confers error-checking and proof-reading capabilities in the self-assembly process within a multi-component reaction system. This review highlights recent progress in the self-assembly of complex organic molecular architectures that are enabled by dynamic imine chemistry, including molecular containers with defined geometry and size, mechanically interlocked molecules, and extended frameworks and polymers, from building blocks with preprogrammed steric and electronic information. The functional aspects associated with the nanometer-scale features not only place these dynamically constructed nanostructures at the frontier of materials sciences, but also bring unprecedented opportunities for the discovery of new functional materials.

scholarly journals Helicase-like functions in phosphate loop containing beta-alpha polypeptides

2021 ◽  
Vol 118 (16) ◽  
pp. e2016131118
Author(s):  
Pratik Vyas ◽  
Olena Trofimyuk ◽  
Liam M. Longo ◽  
Fanindra Kumar Deshmukh ◽  
Michal Sharon ◽  
...  
Keyword(s):  
Phosphoryl Transfer ◽  
Rna Helicases ◽  
Sequence Structure ◽  
Repeat Proteins ◽  
Dynamic Assembly ◽  
Essential Enzyme ◽  
Enzyme Families ◽  
And Function ◽  
Dsdna Binding ◽  
Oligomeric Forms

The P-loop Walker A motif underlies hundreds of essential enzyme families that bind nucleotide triphosphates (NTPs) and mediate phosphoryl transfer (P-loop NTPases), including the earliest DNA/RNA helicases, translocases, and recombinases. What were the primordial precursors of these enzymes? Could these large and complex proteins emerge from simple polypeptides? Previously, we showed that P-loops embedded in simple βα repeat proteins bind NTPs but also, unexpectedly so, ssDNA and RNA. Here, we extend beyond the purely biophysical function of ligand binding to demonstrate rudimentary helicase-like activities. We further constructed simple 40-residue polypeptides comprising just one β-(P-loop)-α element. Despite their simplicity, these P-loop prototypes confer functions such as strand separation and exchange. Foremost, these polypeptides unwind dsDNA, and upon addition of NTPs, or inorganic polyphosphates, release the bound ssDNA strands to allow reformation of dsDNA. Binding kinetics and low-resolution structural analyses indicate that activity is mediated by oligomeric forms spanning from dimers to high-order assemblies. The latter are reminiscent of extant P-loop recombinases such as RecA. Overall, these P-loop prototypes compose a plausible description of the sequence, structure, and function of the earliest P-loop NTPases. They also indicate that multifunctionality and dynamic assembly were key in endowing short polypeptides with elaborate, evolutionarily relevant functions.

scholarly journals Multi-Omics Analysis Identifying Key Biomarkers in Ovarian Cancer

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482097667
Author(s):  
Ju-Yueh Li ◽  
Chia-Jung Li ◽  
Li-Te Lin ◽  
Kuan-Hao Tsui
Keyword(s):  
Ovarian Cancer ◽  
Protein Interactions ◽  
Malignant Tumors ◽  
Single Gene ◽  
Protein Protein Interactions ◽  
Normal Tissues ◽  
Human Protein Atlas ◽  
Copy Number Changes ◽  
And Function ◽  
Cancer Tissues

Ovarian cancer is one of the most common malignant tumors. Here, we aimed to study the expression and function of the CREB1 gene in ovarian cancer via the bioinformatic analyses of multiple databases. Previously, the prognosis of ovarian cancer was based on single-factor or single-gene studies. In this study, different bioinformatics tools (such as TCGA, GEPIA, UALCAN, MEXPRESS, and Metascape) have been used to assess the expression and prognostic value of the CREB1 gene. We used the Reactome and cBioPortal databases to identify and analyze CREB1 mutations, copy number changes, expression changes, and protein–protein interactions. By analyzing data on the CREB1 differential expression in ovarian cancer tissues and normal tissues from 12 studies collected from the “Human Protein Atlas” database, we found a significantly higher expression of CREB1 in normal ovarian tissues. Using this database, we collected information on the expression of 25 different CREB-related proteins, including TP53, AKT1, and AKT3. The enrichment of these factors depended on tumor metabolism, invasion, proliferation, and survival. Individualized tumors based on gene therapy related to prognosis have become a new possibility. In summary, we established a new type of prognostic gene profile for ovarian cancer using the tools of bioinformatics.

scholarly journals Properties of the phage-shock-protein (Psp) regulatory complex that govern signal transduction and induction of the Psp response in Escherichia coli

Microbiology ◽  
2010 ◽  
Vol 156 (10) ◽  
pp. 2920-2932 ◽  
Author(s):  
Goran Jovanovic ◽  
Christoph Engl ◽  
Antony J. Mayhew ◽  
Patricia C. Burrows ◽  
Martin Buck
Keyword(s):  
Escherichia Coli ◽  
Signal Transduction ◽  
Protein Interactions ◽  
Leucine Zipper ◽  
Negative Control ◽  
Stress Conditions ◽  
Bacterial Cells ◽  
Protein Protein Interactions ◽  
Regulatory Complex ◽  
And Function

The phage-shock-protein (Psp) response maintains the proton-motive force (pmf) under extracytoplasmic stress conditions that impair the inner membrane (IM) in bacterial cells. In Escherichia coli transcription of the pspABCDE and pspG genes requires activation of σ 54-RNA polymerase by the enhancer-binding protein PspF. A regulatory network comprising PspF–A–C–B–ArcB controls psp expression. One key regulatory point is the negative control of PspF imposed by its binding to PspA. It has been proposed that under stress conditions, the IM-bound sensors PspB and PspC receive and transduce the signal(s) to PspA via protein–protein interactions, resulting in the release of the PspA–PspF inhibitory complex and the consequent induction of psp. In this work we demonstrate that PspB self-associates and interacts with PspC via putative IM regions. We present evidence suggesting that PspC has two topologies and that conserved residue G48 and the putative leucine zipper motif are determinants required for PspA interaction and signal transduction upon stress. We also establish that PspC directly interacts with the effector PspG, and show that PspG self-associates. These results are discussed in the context of formation and function of the Psp regulatory complex.

scholarly journals Distinct activities of Scrib module proteins organize epithelial polarity

2020 ◽  
Vol 117 (21) ◽  
pp. 11531-11540 ◽  
Author(s):  
Mark J. Khoury ◽  
David Bilder
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Epithelial Polarity ◽  
Protein Protein Interactions ◽  
Kinase C ◽  
Mutual Antagonism ◽  
Discs Large ◽  
Lethal Giant Larvae ◽  
Epithelial Structure ◽  
And Function

A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scribble (Scrib) module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Discs-large (Dlg), and Lethal giant larvae (Lgl) using theDrosophilafollicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein–protein interactions as essential for polarization. Cortical recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize atypical protein kinase C (aPKC), but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg, and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.

scholarly journals Structure and function of human Vps20 and Snf7 proteins

2004 ◽  
Vol 377 (3) ◽  
pp. 693-700 ◽  
Author(s):  
Jeremy W. PECK ◽  
Emma T. BOWDEN ◽  
Peter D. BURBELO
Keyword(s):  
Protein Interactions ◽  
Osmotic Shock ◽  
Multivesicular Body ◽  
Protein Protein Interactions ◽  
Interacting Protein ◽  
Endosomal Membrane ◽  
Genomic Studies ◽  
Vacuolar Protein ◽  
And Function

Snf7p (sucrose non-fermenting) and Vps20p (vacuolar protein-sorting) are small coil-coiled proteins involved in yeast MVB (multivesicular body) structure, formation and function. In the present study, we report the identification of three human homologues of yeast Snf7p, designated hSnf7-1, hSnf7-2 and hSnf7-3, and a single human Vps20p homologue, designated hVps20, that may have similar roles in humans. Immunofluorescence studies showed that hSnf7-1 and hSnf7-3 localized in large vesicular structures that also co-localized with late endosomal/lysosomal structures induced by overexpressing an ATPase-defective Vps4-A mutant. In contrast, overexpressed hVps20 showed a typical endosomal membrane-staining pattern, and co-expression of hVps20 with Snf7-1 dispersed the large Snf7-staining vesicles. Interestingly, overexpression of both hSnf7 and hVps20 proteins induced a post-endosomal defect in cholesterol sorting. To explore possible protein–protein interactions involving hSnf7 proteins, we used information from yeast genomic studies showing that yeast Snf7p can interact with proteins involved in MVB function. Using a glutathione S-transferase-capture approach with several mammalian homologues of such yeast Snf7p-interacting proteins, we found that all three hSnf7s interacted with mouse AIP1 [ALG-2 (apoptosis-linked gene 2) interacting protein 1], a mammalian Bro1p [BCK1 (bypass of C kinase)-like resistance to osmotic shock]-containing protein involved in cellular vacuolization and apoptosis. Whereas mapping experiments showed that the N-terminus of AIP1 containing both a Bro1 and an α-helical domain were required for interaction with hSnf7-1, Snf7-1 did not interact with another human Bro1-containing molecule, rhophilin-2. Co-immunoprecipitation experiments confirmed the in vivo interaction of hSnf7-1 and AIP1. Additional immunofluorescence experiments showed that hSnf7-1 recruited cytosolic AIP1 to the Snf7-induced vacuolar-like structures. Together these results suggest that mammalian Vps20, AIP1 and Snf7 proteins, like their yeast counterparts, play roles in MVB function.

scholarly journals DNA-mediated engineering of multicomponent enzyme crystals

2015 ◽  
Vol 112 (15) ◽  
pp. 4564-4569 ◽  
Author(s):  
Jeffrey D. Brodin ◽  
Evelyn Auyeung ◽  
Chad A. Mirkin
Keyword(s):  
Gold Nanoparticles ◽  
Protein Interactions ◽  
Building Blocks ◽  
Inorganic Nanoparticles ◽  
Protein Protein Interactions ◽  
Dna Interactions ◽  
Interparticle Interactions ◽  
Crystalline Materials ◽  
Catalytically Active ◽  
Surface Chemistries

The ability to predictably control the coassembly of multiple nanoscale building blocks, especially those with disparate chemical and physical properties such as biomolecules and inorganic nanoparticles, has far-reaching implications in catalysis, sensing, and photonics, but a generalizable strategy for engineering specific contacts between these particles is an outstanding challenge. This is especially true in the case of proteins, where the types of possible interparticle interactions are numerous, diverse, and complex. Herein, we explore the concept of trading protein–protein interactions for DNA–DNA interactions to direct the assembly of two nucleic-acid–functionalized proteins with distinct surface chemistries into six unique lattices composed of catalytically active proteins, or of a combination of proteins and DNA-modified gold nanoparticles. The programmable nature of DNA–DNA interactions used in this strategy allows us to control the lattice symmetries and unit cell constants, as well as the compositions and habit, of the resulting crystals. This study provides a potentially generalizable strategy for constructing a unique class of materials that take advantage of the diverse morphologies, surface chemistries, and functionalities of proteins for assembling functional crystalline materials.

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