A5066141945- Bioinformatics and Genomic Networks
- Protein Kinase Regulation and GTPase Signaling
- Computational Drug Discovery Methods
- Genomics and Phylogenetic Studies
- Microtubule and mitosis dynamics
- Protein Structure and Dynamics
- Machine Learning in Bioinformatics
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- 14-3-3 protein interactions
- Genomics, phytochemicals, and oxidative stress
- Advanced biosensing and bioanalysis techniques
- Fungal and yeast genetics research
- Phytochemicals and Antioxidant Activities
- Metabolism, Diabetes, and Cancer
- Genomics and Chromatin Dynamics
- Endoplasmic Reticulum Stress and Disease
- Enzyme Structure and Function
- Microbial Natural Products and Biosynthesis
- Cell death mechanisms and regulation
- bioluminescence and chemiluminescence research
- DNA and Nucleic Acid Chemistry
- Amino Acid Enzymes and Metabolism
- Sirtuins and Resveratrol in Medicine
- Enzyme Production and Characterization
University of Georgia
2016-2025
University of Liverpool
2023-2024
Lingnan University
2006
University of Hong Kong
2005
Pseudokinases are prevalent across species and contribute diverse, noncatalytic signaling functions.
Phosphorylation of an evolutionarily conserved motif by mTORC2 enables the maturation AGC kinases.
Phosphorylation of the MLKL pseudokinase by RIPK3 kinase leads to oligomerization, translocation to, and permeabilization of, plasma membrane induce necroptotic cell death. The precise choreography activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind domain within human cells their crystal structures in complex with domain. While Monobody-32 constitutively binds hinge region, Monobody-27 via an epitope overlaps site is only exposed...
Glycosyltransferases (GTs) are prevalent across the tree of life and regulate nearly all aspects cellular functions. The evolutionary basis for their complex diverse modes catalytic functions remain enigmatic. Here, based on deep mining over half million GT-A fold sequences, we define a minimal core component shared among functionally enzymes. We find that variations in common emergence hypervariable loops extending from contributed to diversity. provide phylogenetic framework relating...
Covalent EGFR family inhibitors bind to and induce the degradation of pseudokinase TRIB2 kill cancer cells.
We describe the application of T4 DNA ligase-catalyzed templated oligonucleotide polymerization toward evolution a diversely functionalized nucleic acid aptamer for human α-thrombin. Using 256-membered ANNNN comonomer library comprising 16 sublibraries modified with different functional groups, highly thrombin was raised dissociation constant 1.6 nM. The found to be selective and required modifications binding affinity. This study demonstrates most differentially discovered by in vitro...
Abstract The MLKL pseudokinase is the terminal effector in necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL’s conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, plasma membrane to kill cells. precise mechanisms underlying these processes are incompletely understood, were proposed differ between mouse human Here, we examine divergence of activation among nine vertebrate orthologues, revealing...
The faithful propagation of cellular signals in most organisms relies on the coordinated functions a large family protein kinases that share conserved catalytic domain. domain is dynamic scaffold undergoes conformational changes upon activation. Most these changes, such as movement regulatory αC-helix from an "out" to "in" conformation, hinge conserved, but understudied, loop termed αC-β4 loop, which mediates interactions tether flexible structural elements kinase core. We previously showed...
Abstract Glycosyltransferases (GTs) play fundamental roles in nearly all cellular processes through the biosynthesis of complex carbohydrates and glycosylation diverse protein small molecule substrates. The extensive structural functional diversification GTs presents a major challenge mapping relationships connecting sequence, structure, fold function using traditional bioinformatics approaches. Here, we present convolutional neural network with attention (CNN-attention) based deep learning...
Protein language modeling is a fast-emerging deep learning method in bioinformatics with diverse applications such as structure prediction and protein design. However, application toward estimating sequence conservation for functional site has not been systematically explored. Here, we present the alignment-free estimation of using embeddings generated from models. Comprehensive benchmarks across publicly available models reveal that ESM2 provide best performance to computational cost ratio...
The human genome encodes over 500 distinct protein kinases which regulate nearly all cellular processes by the specific phosphorylation of substrates. While advances in mass spectrometry and proteomics studies have identified thousands sites across species, information on that phosphorylate these is currently lacking for vast majority phosphosites. Recently, there has been a major focus development computational models predicting kinase-substrate associations. However, most current only...
Bacterial serine-threonine protein kinases (STKs) regulate diverse cellular processes associated with cell growth, virulence, and pathogenicity. They are evolutionarily related to the druggable eukaryotic STKs. However, an incomplete knowledge of how bacterial STKs differ from their counterparts they have diverged signaling functions presents a bottleneck in targeting them for drug discovery efforts. Here, we classified over 300,000 STK sequences NCBI RefSeq non-redundant UniProt databases...
In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications, including phosphorylation Ser/Thr residues and oxidation cysteine (Cys) residues. While regulation activation segment well understood, relatively little known about how modulate catalysis. this study, we investigate redox the AMPK-related brain-selective kinases (BRSK) 1 2, detail broad catalytic activity directly through reversible reduction evolutionarily conserved Cys within...
Protein language models, trained on millions of biologically observed sequences, generate feature-rich numerical representations protein sequences. These representations, called sequence embeddings, can infer structure-functional properties, despite models being primary alone. While embeddings have been applied toward tasks such as structure and function prediction, applications alignment-free classification hindered by the lack studies to derive, quantify evaluate relationships between...
The current understanding of farnesyltransferase (FTase) specificity was pioneered through investigations reporters like Ras and Ras-related proteins that possess a C-terminal CaaX motif consists 4 amino acid residues: cysteine-aliphatic1-aliphatic2-variable (X). These studies led to the finding with are subject 3-step post-translational modification pathway involving farnesylation, proteolysis, carboxylmethylation. Emerging evidence indicates, however, FTase can farnesylate sequences...
The emergence of multicellularity is strongly correlated with the expansion tyrosine kinases, a conserved family signaling enzymes that regulates pathways essential for cell-to-cell communication. Although kinases have been classified from several model organisms, molecular-level understanding kinase evolution across all holozoans currently lacking. Using hierarchical sequence constraint-based classification diverse holozoan we construct new phylogenetic tree identifies two ancient clades...
Abstract Aurora-A is an essential cell-cycle kinase with critical roles in mitotic entry and spindle dynamics. These functions require binding partners such as CEP192 TPX2, which modulate both activity localisation of Aurora-A. Here we investigate the structure role centrosomal Aurora-A:CEP192 complex wider molecular network. We find that wraps around Aurora-A, occupies sites for spindle-associated partners, thus competes them. Comparison two different conformations reveals how modifies...
The homeodomain-interacting protein kinase (HIPK) family is comprised of four nuclear kinases, HIPK1-4. HIPK proteins phosphorylate a diverse range transcription factors involved in cell proliferation, differentiation, and apoptosis. HIPK2, thus far the best-characterized member this largely understudied plays role activation p53 response to DNA damage. Despite tumor-suppressor function, HIPK2 also found overexpressed several cancers, its hyperactivation causes chronic fibrosis. There are...
Protein kinases are among the largest druggable family of signaling proteins, involved in various human diseases, including cancers and neurodegenerative disorders. Despite their clinical relevance, nearly 30% 545 protein remain highly understudied. Comparative genomics is a powerful approach for predicting investigating functions understudied kinases. However, an incomplete knowledge kinase orthologs across fully sequenced kinomes severely limits application comparative approaches...
The development and in-depth analysis of T4 DNA ligase-catalyzed templated oligonucleotide polymerization toward the generation diversely functionalized nucleic acid polymers is described. NNNNT codon set enables low bias, high fidelity, efficiency for ANNNN libraries comprising various functional groups. robustness method was highlighted in copolymerization a 256-membered library 16 sub-libraries modified with different This enabled synthetic polymer 93.8 % fidelity. process should find...
Significance Bruton’s tyrosine kinase (BTK) is targeted in treatment of immune cancers. As patients experience drug resistance, there a need for alternative approaches to inhibit BTK. Other recently published findings clarify the role BTK pleckstrin homology (PH) domain mediating activation via dimerization and sensing ligand concentration at membrane. Work presented here provides insight into autoinhibitory structure that has so far been elusive crystallographic methods. In resting state,...
Abstract Motivation Phosphorylation, a post-translational modification regulated by protein kinase enzymes, plays an essential role in almost all cellular processes. Understanding how each of the nearly 500 human kinases selectively phosphorylates their substrates is foundational challenge bioinformatics and cell signaling. Although deep learning models have been popular means to predict kinase–substrate relationships, existing often lack interpretability are trained on datasets skewed...
Catalytic signaling outputs of protein kinases are dynamically regulated by an array structural mechanisms, including allosteric interactions mediated intrinsically disordered segments flanking the conserved catalytic domain. The doublecortin-like (DCLKs) a family microtubule-associated proteins characterized flexible C-terminal autoregulatory 'tail' segment that varies in length across various human DCLK isoforms. However, mechanism whereby these isoform-specific variations contribute to...
The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function, and disease in a human machine-readable format. In this study, we have significantly expanded ProKinO by incorporating additional data on expression patterns drug interactions. Furthermore, developed completely new browser from ground up to render visible interactive web. We enriched with classes capture information ligand...