A5053025310- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
- Retinal Development and Disorders
- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Fetal and Pediatric Neurological Disorders
- Hippo pathway signaling and YAP/TAZ
- Erythrocyte Function and Pathophysiology
- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- Lipid Membrane Structure and Behavior
- Microtubule and mitosis dynamics
- T-cell and B-cell Immunology
- Retinal and Macular Surgery
- CAR-T cell therapy research
- Chemical Synthesis and Analysis
- Neonatal and fetal brain pathology
- Advanced Fluorescence Microscopy Techniques
- Adipose Tissue and Metabolism
- Trace Elements in Health
- Mitochondrial Function and Pathology
- Calcium signaling and nucleotide metabolism
- Cell Image Analysis Techniques
- Glycosylation and Glycoproteins Research
- RNA regulation and disease
MRC Laboratory of Molecular Biology
2021-2025
University of Bristol
2016-2024
Abstract Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive folding macromolecular interactions 1 . Reciprocally, macromolecules restrict the movement of ‘structured’ molecules within their hydration layers, reducing available ‘free’ bulk therefore total thermodynamic potential energy water, or potential. Here, concentrated solutions such as cytosol, we found that modest changes in temperature greatly affect...
The Commander complex is required for endosomal recycling of diverse transmembrane cargos and mutated in Ritscher-Schinzel syndrome. It comprises two sub-assemblies: Retriever composed VPS35L, VPS26C, VPS29; the CCC which contains twelve subunits: COMMD1-COMMD10 coiled-coil domain-containing (CCDC) proteins CCDC22 CCDC93. Combining X-ray crystallography, electron cryomicroscopy, silico predictions, we have assembled a complete structural model Commander. distantly related to Retromer but has...
Abstract General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, is challenging, as most peptides do not defined structures isolation, hydrogen bonds must be made to the buried polar groups peptide backbone 1–3 . Here, inspired by natural re-engineered protein–peptide systems 4–11 , we set out design of repeating units that bind with sequences, a one-to-one correspondence between repeat protein those...
Elongator is a tRNA-modifying complex that regulates protein translation. Recently, moonlighting function of has been identified in regulating the polarization microtubule cytoskeleton during asymmetric cell division. induces symmetry breaking anaphase midzone by selectively stabilizing microtubules on one side spindle, contributing to downstream polarized segregation cell-fate determinants, and therefore fate determination. Here, we investigate how controls dynamics. binds both tip free...
A general approach to design proteins that bind tightly and specifically intrinsically disordered regions (IDRs) of flexible peptides would have wide application in biological research, therapeutics, diagnosis. However, the lack defined structures high variability sequence conformational preferences has complicated such efforts. We sought develop a method combining biophysical principles with deep learning readily generate binders for any sequence. Instead assuming fixed regular structure...
Abstract Multispectral imaging is an established method to extend the number of colours usable in fluorescence beyond typical limit three or four, but standard approaches are poorly suited live-cell imaging. We introduce approach for multispectral live cells, comprising iterative spectral unmixing algorithm and eight channel camera-based image acquisition hardware. This enables accurate low signal-to-noise ratio datasets, imaging, captured at video rates. use this on a commercial spinning...
Abstract Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and essential for normal development. While the structure this has recently been described, how are selected Commander-mediated remains unclear. Here we identify mechanism through which unstructured carboxy-terminal tail adaptor sorting nexin-17 (SNX17) directly binds to Retriever sub-complex Commander. SNX17 adopts an autoinhibited conformation where its occupies binding groove....
Abstract Commander is an endosome associated sixteen protein assembly that associates with the sorting nexin 17 (SNX17) cargo adaptor to regulate cell surface recycling of internalised integral membrane proteins including integrins and lipoprotein receptors. Mutations in are causative for Ritscher-Schinzel syndrome (RSS), a multiorgan developmental disease core triad cerebellar-cardiac-craniofacial malformation. Here, using unbiased proteomics computational modelling, we identify leucine...
ABSTRACT Commander is a multiprotein complex that orchestrates endosomal recycling of diverse integral cargo proteins and in humans required for normal skeletal, brain, kidney, cardiovascular development. While the structure this has recently been described, central question how are selected entry into pathway remains unclear. Here using recombinant protein reconstitution silico predictions we identify evolutionary conserved mechanism through which unstructured carboxy-terminal tail adaptor...
Notch is a critical regulator of T cell differentiation and activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 cells, we demonstrate that proximal signaling modulates activation by spatiotemporally constrained mechanism. The protein kinase PKCθ mediator the antigen receptor principal costimulatory CD28. selectively inactivates negative F-actin generation, Coronin 1A, at center interface with presenting (APC). This allows for effective...
Elongator is a tRNA-modifying complex that regulates the fidelity of protein translation. Recently, moonlighting function has been identified in regulating polarization microtubule cytoskeleton during asymmetric cell division. induces symmetry breaking anaphase midzone by selectively stabilizing microtubules on one side spindle. This polarizes segregation signalling endosomes containing cell-fate determinants to only daughter cell, thus contributing fate determination. Here, we unravelled...
Abstract General approaches for designing sequence-specific peptide binding proteins would have wide utility in proteomics and synthetic biology. Although considerable progress has been made which bind to other proteins, the general problem is more challenging as most peptides do not defined structures isolation, offset loss solvation upon protein interface provide specific hydrogen bonds that complement majority of buried peptide’s backbone polar groups ( 1 – 3 ). Inspired by natural repeat...
Abstract The sorting nexin SNX17 controls endosome-to-cell surface recycling of diverse transmembrane cargo proteins including integrins, the amyloid precursor protein and lipoprotein receptors. This requires association with multi-subunit Commander trafficking complex, which depends on C-terminus through unknown mechanisms. Using affinity enrichment proteomics, we find that a C-terminal peptide is not only sufficient for interaction but also associates members actin-associated PDZ LIM...
SUMMARY The Commander complex is required for endosomal recycling of diverse transmembrane cargos and mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed VPS35L, VPS26C VPS29, the CCC which contains ten subunits COMMD1-COMMD10 coiled-coil domain-containing (CCDC) proteins CCDC22 CCDC93. Combining X-ray crystallography, electron cryomicroscopy silico predictions we have assembled a complete structural model Commander. distantly related to Retromer but has...
The Commander complex is required for endosomal recycling of diverse transmembrane cargos and mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed VPS35L, VPS26C VPS29, the CCC which contains ten subunits COMMD1-COMMD10 coiled-coil domain-containing (CCDC) proteins CCDC22 CCDC93. Combining X-ray crystallography, electron cryomicroscopy silico predictions we have assembled a complete structural model Commander. distantly related to Retromer but has unique...
The sorting nexin SNX17 controls endosome-to-cell surface recycling of diverse transmembrane cargo proteins including integrins, the amyloid precursor protein and lipoprotein receptors. This requires association with multi-subunit Commander trafficking complex, which depends on C-terminus through unknown mechanisms. Using affinity enrichment proteomics, we find that a C-terminal peptide is not only sufficient for interaction but also associates members actin-associated PDZ LIM domain (PDLIM)...