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Biomolecules Nov 2022The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins play a central role in most forms of intracellular membrane... (Review)
Review
The soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins play a central role in most forms of intracellular membrane trafficking, a key process that allows for membrane and biocargo shuffling between multiple compartments within the cell and extracellular environment. The structural organization of SNARE proteins is relatively simple, with several intrinsically disordered and folded elements (e.g., SNARE motif, N-terminal domain, transmembrane region) that interact with other SNAREs, SNARE-regulating proteins and biological membranes. In this review, we discuss recent advances in the development of functional peptides that can modify SNARE-binding interfaces and modulate SNARE function. The ability of the relatively short SNARE motif to assemble spontaneously into stable coiled coil tetrahelical bundles has inspired the development of reduced SNARE-mimetic systems that use peptides for biological membrane fusion and for making large supramolecular protein complexes. We evaluate two such systems, based on peptide-nucleic acids (PNAs) and coiled coil peptides. We also review how the self-assembly of SNARE motifs can be exploited to drive on-demand assembly of complex re-engineered polypeptides.
Topics: SNARE Proteins; Membrane Fusion; Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; Protein Binding; Peptides
PubMed: 36551207
DOI: 10.3390/biom12121779 -
Organic Letters Jul 2022Forging new C(sp)-C(sp) bonds to central positions within a peptide backbone is critical for the development of new therapeutics and chemical probes. Currently, there...
Forging new C(sp)-C(sp) bonds to central positions within a peptide backbone is critical for the development of new therapeutics and chemical probes. Currently, there are no methods for decarboxylating Asp and Glu side chains solid-phase photochemically or using such radicals to form peptide macrocycles. Herein, electron-donor-acceptor complexes between Hantzsch ester and on-resin peptide -hydroxyphthalimide radical precursors are used to access these radicals, demonstrated with two-carbon homologations and homologation cyclizations of Atosiban and RGDf.
Topics: Cyclization; Esters; Peptides
PubMed: 35816696
DOI: 10.1021/acs.orglett.2c02012 -
Angewandte Chemie (International Ed. in... Jan 2024Proteolysis targeting chimera (PROTAC) is a state-of-the-art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD)... (Review)
Review
Proteolysis targeting chimera (PROTAC) is a state-of-the-art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril-based PROTAC strategy to form a polynary (E3) : PROTAC : (POI) complex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self-assembly-driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so-called Nano-PROTAC provides a novel approach for TPD in cancer therapy.
Topics: Proteolysis; Ligands; Ubiquitin-Protein Ligases; Peptides
PubMed: 38059785
DOI: 10.1002/anie.202316581 -
American Journal of Physiology.... Oct 2020Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have... (Review)
Review
Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA () gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1-6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease.
Topics: Animals; Energy Metabolism; Humans; Mitochondria; Mitochondrial Proteins; Peptides
PubMed: 32776825
DOI: 10.1152/ajpendo.00249.2020 -
Angewandte Chemie (International Ed. in... Apr 2022Lipidation is a ubiquitous modification of peptides and proteins that can occur either co- or post-translationally. An array of different lipid classes can adorn... (Review)
Review
Lipidation is a ubiquitous modification of peptides and proteins that can occur either co- or post-translationally. An array of different lipid classes can adorn proteins and has been shown to influence a number of crucial biological activities, including the regulation of signaling, cell-cell adhesion events, and the anchoring of proteins to lipid rafts and phospholipid membranes. Whereas nature employs a range of enzymes to install lipid modifications onto proteins, the use of these for the chemoenzymatic generation of lipidated proteins is often inefficient or impractical. An alternative is to harness the power of modern synthetic and semisynthetic technologies to access lipid-modified proteins in a pure and homogeneously modified form. This Review aims to highlight significant advances in the development of lipidation and ligation chemistry and their implementation in the synthesis and semisynthesis of homogeneous lipidated proteins that have enabled the influence of these modifications on protein structure and function to be uncovered.
Topics: Lipid Metabolism; Lipids; Peptides; Proteins
PubMed: 34611966
DOI: 10.1002/anie.202111266 -
Nature Apr 2023General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing...
General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing peptide-binding proteins is challenging, as most peptides do not have defined structures in isolation, and hydrogen bonds must be made to the buried polar groups in the peptide backbone. Here, inspired by natural and re-engineered protein-peptide systems, we set out to design proteins made out of repeating units that bind peptides with repeating sequences, with a one-to-one correspondence between the repeat units of the protein and those of the peptide. We use geometric hashing to identify protein backbones and peptide-docking arrangements that are compatible with bidentate hydrogen bonds between the side chains of the protein and the peptide backbone. The remainder of the protein sequence is then optimized for folding and peptide binding. We design repeat proteins to bind to six different tripeptide-repeat sequences in polyproline II conformations. The proteins are hyperstable and bind to four to six tandem repeats of their tripeptide targets with nanomolar to picomolar affinities in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including ladders of hydrogen bonds from protein side chains to peptide backbones. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating peptide sequences and for disordered regions of native proteins.
Topics: Amino Acid Sequence; Models, Molecular; Peptides; Proteins; Protein Engineering; Hydrogen Bonding; Protein Binding; Protein Folding; Protein Conformation
PubMed: 37020023
DOI: 10.1038/s41586-023-05909-9 -
Biomolecules Jan 2021Since the isolation and commercialization of insulin (a peptide composed of 51 amino acid residues) in the early 1920s, peptide drugs have reshaped the pharmaceutical...
Since the isolation and commercialization of insulin (a peptide composed of 51 amino acid residues) in the early 1920s, peptide drugs have reshaped the pharmaceutical industry [...].
Topics: Animals; Biotechnology; Fermentation; Genomics; Humans; Nanotechnology; Peptide Hydrolases; Peptides
PubMed: 33401441
DOI: 10.3390/biom11010052 -
Biochemical Society Transactions Nov 2021Human leukocyte antigens (HLA) are cell-surface proteins that present peptides to T cells. These peptides are bound within the peptide binding cleft of HLA, and together... (Review)
Review
Human leukocyte antigens (HLA) are cell-surface proteins that present peptides to T cells. These peptides are bound within the peptide binding cleft of HLA, and together as a complex, are recognised by T cells using their specialised T cell receptors. Within the cleft, the peptide residue side chains bind into distinct pockets. These pockets ultimately determine the specificity of peptide binding. As HLAs are the most polymorphic molecules in humans, amino acid variants in each binding pocket influences the peptide repertoire that can be presented on the cell surface. Here, we review each of the 6 HLA binding pockets of HLA class I (HLA-I) molecules. The binding specificity of pockets B and F are strong determinants of peptide binding and have been used to classify HLA into supertypes, a useful tool to predict peptide binding to a given HLA. Over the years, peptide binding prediction has also become more reliable by using binding affinity and mass spectrometry data. Crystal structures of peptide-bound HLA molecules provide a means to interrogate the interactions between binding pockets and peptide residue side chains. We find that most of the bound peptides from these structures conform to binding motifs determined from prediction software and examine outliers to learn how these HLAs are stabilised from a structural perspective.
Topics: Amino Acid Sequence; Crystallography, X-Ray; Histocompatibility Antigens Class I; Humans; Peptides; Protein Binding
PubMed: 34581761
DOI: 10.1042/BST20210410 -
Current Opinion in Chemical Biology Jun 2024Novel discoveries in natural product biosynthesis reveal hidden bioactive compounds and expand our knowledge in enzymology. Ribosomally synthesized and... (Review)
Review
Novel discoveries in natural product biosynthesis reveal hidden bioactive compounds and expand our knowledge in enzymology. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly growing class of natural products featuring diverse non-canonical amino acids introduced by maturation enzymes as a class-defining characteristic. Underexplored RiPP sources, such as the human microbiome, the oceans, uncultured microorganisms, and plants are rich hunting grounds for novel enzymology. Unusual α- and β-amino acids, peptide cleavages, lipidations, diverse macrocyclizations, and other features expand the range of chemical groups that are installed in RiPPs by often promiscuous enzymes. This review highlights the search for novelty in RiPP enzymology in the past two years, with respect to the discovery of new biochemical modifications but also towards novel applications.
Topics: Protein Processing, Post-Translational; Humans; Peptides; Ribosomes; Biological Products; Animals; Enzymes
PubMed: 38729090
DOI: 10.1016/j.cbpa.2024.102463 -
Biomolecules Nov 2023Despite significant strides in prevention, diagnosis, and treatment, cardiovascular diseases remain the number one cause of mortality in the United States, with rates... (Review)
Review
Despite significant strides in prevention, diagnosis, and treatment, cardiovascular diseases remain the number one cause of mortality in the United States, with rates climbing at an alarming rate in the developing world. Targeted delivery of therapeutics to the heart has been a lofty goal to achieve with strategies ranging from direct intra-cardiac or intra-pericardial delivery, intra-coronary infusion, to adenoviral, lentiviral, and adeno-associated viral vectors which have preference, if not complete cardio-selectivity, for cardiac tissue. Cell-penetrating peptides (CPP) are 5-30-amino-acid-long peptides that are able to breach cell membrane barriers while carrying cargoes up to several times their size, in an intact functional form. Identified nearly three decades ago, the first of these CPPs came from the HIV coat protein transactivator of transcription. Although a highly efficient CPP, its clinical utility is limited by its robust ability to cross any cell membrane barrier, including crossing the blood-brain barrier and transducing neuronal tissue non-specifically. Several strategies have been utilized to identify cell- or tissue-specific CPPs, one of which is phage display. Using this latter technique, we identified a cardiomyocyte-targeting peptide (CTP) more than a decade ago, a finding that has been corroborated by several independent labs across the world that have utilized CTP for a myriad of different purposes in pre-clinical animal models. The goal of this publication is to provide a comprehensive review of the identification, validation, and application of CTP, and outline its potential in diagnostic and therapeutic applications especially in the field of targeted RNA interference.
Topics: Animals; Cell-Penetrating Peptides; Biological Transport; Heart; Cell Membrane
PubMed: 38136562
DOI: 10.3390/biom13121690