A5021948242- Cardiomyopathy and Myosin Studies
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Force Microscopy Techniques and Applications
- Muscle Physiology and Disorders
- Microtubule and mitosis dynamics
- Cellular transport and secretion
- Monoclonal and Polyclonal Antibodies Research
- Ubiquitin and proteasome pathways
- Cellular Mechanics and Interactions
- Protein Kinase Regulation and GTPase Signaling
- RNA Research and Splicing
- Nuclear Structure and Function
- Cardiovascular Effects of Exercise
- Signaling Pathways in Disease
- Cell Adhesion Molecules Research
- Wnt/β-catenin signaling in development and cancer
- Erythrocyte Function and Pathophysiology
- Toxin Mechanisms and Immunotoxins
- Ion channel regulation and function
- Mitochondrial Function and Pathology
- Photosynthetic Processes and Mechanisms
- Glycosylation and Glycoproteins Research
- Advanced NMR Techniques and Applications
King's College London
2015-2025
British Heart Foundation
2023
King's College School
2023
University of Leicester
2002-2013
University College London
1998-2002
Ludwig Cancer Research
2000-2002
UCL Australia
2001
European Molecular Biology Organization
1995-1997
European Molecular Biology Laboratory
1996-1997
MRC Laboratory of Molecular Biology
1996
Myosin-binding protein C (MyBP-C) is a multidomain present in the thick filaments of striated muscles and involved both sarcomere formation contraction regulation. The latter function believed to be located at N terminus, which close motor domain myosin. cardiac isoform MyBP-C linked hypertrophic cardiomyopathy. Here, we use NMR spectroscopy biophysical biochemical assays study three-dimensional structure interactions cardiac-specific Ig-like C0, part little known. confirmed that C0 member...
Acomplex of transforming acidic coiled-coil protein 3 (TACC3), colonic and hepatic tumor overexpressed gene (ch-TOG), clathrin has been implicated in mitotic spindle assembly the stabilization kinetochore fibers by cross-linking microtubules. It is unclear how this complex binds microtubules proteins interact with one another. TACC3 have each proposed to be recruitment factor. We mapped interactions within show that were interdependent for recruitment, having order either recruited spindle....
Abstract Mutations in the sarcomeric protein titin, encoded by TTN , are emerging as a common cause of myopathies. The diagnosis -related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and prevalence variants control populations. Here, we present combined clinico-pathological, genetic biophysical approach pathogenicity ascertainment missense variants. We identified 30 patients primary congenital (CM) two truncating variants, or one...
Myosin binding protein C (MyBP-C) is a thick filament involved in the regulation of muscle contraction. Mutations gene for MyBP-C are second most frequent cause hypertrophic cardiomyopathy. binds to myosin with two sites, one at its C-terminus and another N-terminus. The N-terminal site, consisting immunoglobulin domains C1 C2 connected by flexible linker, interacts S2 segment phosphorylation-regulated manner. It assumed that function act as tether fixes S1 heads resting position...
Aurora-A regulates the recruitment of TACC3 to mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe structural basis these interactions, mediated by three motifs in disordered region TACC3. A hydrophobic docking motif binds previously uncharacterized pocket on that is blocked most kinases. Abrogation causes delay late mitosis, consistent cellular distribution complexes. Phosphorylation Ser558 engages conformational switch second from...
The essential mammalian gene TACC3 is frequently mutated and amplified in cancers its fusion products exhibit oncogenic activity glioblastomas. functions mitotic spindle assembly chromosome segregation. In particular, phosphorylation on S558 by the kinase, Aurora-A, promotes recruitment of triggers formation a complex with ch-TOG-clathrin that crosslinks stabilises kinetochore microtubules. Here we map Aurora-A-binding interface show potently activates Aurora-A through domain centered F525....
Förster resonance energy transfer (FRET) is a powerful technique for probing molecular interactions and conformational changes in biological systems. Cascade-FRET, multistep system involving three fluorophores, enables spatial temporal mapping of interactions. Here, we leveraged Cascade-FRET with time-correlated single photon counting fluorescence lifetime imaging microscopy (TCSPC-FLIM) to explore the putative interaction between Rap1-interacting Adapter Molecule (RIAM) vinculin focal...
The mitotic spindle is a bipolar array of microtubules, radiating from the poles which each contain centrosome, embedded in pericentriolar material. Two proteins, ch-TOG and TACC3, have multiple functions at due to operating either alone, together, or complex with other proteins. To distinguish these activities, we need new molecular tools dissect their function. Here, present structure α-helical bundle domain that mediates its interaction TACC3 structural model describing interaction,...
Titin is a 3-MDa protein thought to form fibrous intracellular system in vertebrate striated muscle and play an important role sarcomere alignment during contraction. It has also been implicated as "molecular ruler", regulating the assembly precise length of thick filaments [Whiting, A. J., Wardale, & Trinick, J. (1989) Mol. Biol. 205, 163-169]. Partial sequencing titin-encoding cDNAs suggests that organized modular fashion, containing two classes approximately 100-residue repeats [Labeit,...
Myosin-binding protein C (MyBP-C) binds to myosin with two binding sites, one close the N terminus and other at terminus. Here we present solution structure of part N-terminal site, third immunoglobulin domain cardiac isoform human MyBP-C (cC2) together a model its interaction myosin. Domain cC2 has beta-sandwich expected from member fold. The C-terminal is very closely related telokin, fragment light chain kinase. also contains cysteines on neighboring strands F G, which would be able form...
Spectrin, a major component of the membrane skeleton, is mainly composed tandemly repeated segments approx. 106 amino acids. We have undertaken determination three‐dimensional structure chicken brain α‐spectrin repeat by heteronuclear multidimensional NMR. Sedimentation equilibrium demonstrates that this monomeric at concentration used for NMR (1 mM). Its secondary was identified using collection sequential and medium range NOEs, chemical shifts, HN‐Hα coupling constants, relaxation...
Nesprin-1 and nesprin-2 are nuclear envelope (NE) proteins characterized by a common structure of an SR (spectrin repeat) rod domain C-terminal transmembrane KASH [Klarsicht-ANC-Syne-homology] display N-terminal actin-binding CH (calponin homology) domains. Mutations in these have been described Emery-Dreifuss muscular dystrophy attributed to disruptions interactions at the NE with nesprins binding partners, lamin A/C emerin. Evolutionary analysis domains has shown that they almost entirely...
Leucine zippers are oligomerization domains used in a wide range of proteins. Their structure is based on highly conserved heptad repeat sequence which two key positions occupied by leucines. The leucine zipper the cell cycle-regulated Nek2 kinase important for its dimerization and activation. However, this most unusual that leucines occupy only one hydrophobic positions. other position, depending register repeat, either acidic or basic residues. Using NMR spectroscopy, we show exists...
Abstract The Popeye domain containing (POPDC) genes encode sarcolemma-localized cAMP effector proteins. Mutations in blood vessel epicardial substance ( BVES ) also known as POPDC1 and POPDC2 have been associated with limb-girdle muscular dystrophy cardiac arrhythmia. Muscle biopsies of affected patients display impaired membrane trafficking both POPDC isoforms. Biopsy material carrying mutations were immunostained antibodies. interaction proteins was investigated by co-precipitation,...
The giant muscle proteins of the titin family, which are specific for striated muscles vertebrates and invertebrates, contain as a common feature catalytic protein kinase domain so far unclear function regulation. In myosin light chain kinase, family evolutionarily related to titin, regulation is achieved by calmodulin binding region C-terminus bears similarity substrate. A calmodulin-binding sequence has also been identified in Aplysia twitchin kinase. analogy, we putative site C-terminal...
Abstract The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins thereby controls diverse cellular functions. A number these are implicated in cancer-relevant processes, including Wnt/β-catenin signalling, Hippo signalling telomere maintenance. ARCs recognise conserved tankyrase-binding peptide motif (TBM). All currently available inhibitors target the catalytic domain inhibit tankyrase’s poly(ADP-ribosyl)ation...