A5029279901- Wnt/β-catenin signaling in development and cancer
- Axon Guidance and Neuronal Signaling
- Protein Structure and Dynamics
- Cancer-related gene regulation
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
- Neuroscience and Neuropharmacology Research
- Glycosylation and Glycoproteins Research
- Erythrocyte Function and Pathophysiology
- Peptidase Inhibition and Analysis
- RNA Research and Splicing
- Signaling Pathways in Disease
- Cellular transport and secretion
- Crystallography and molecular interactions
- Receptor Mechanisms and Signaling
- Atmospheric chemistry and aerosols
- Chemical Synthesis and Analysis
- Retinal Development and Disorders
- Enzyme Structure and Function
- Cytokine Signaling Pathways and Interactions
- Carbohydrate Chemistry and Synthesis
- HER2/EGFR in Cancer Research
- Magnesium Alloys: Properties and Applications
- Cancer, Hypoxia, and Metabolism
- Nicotinic Acetylcholine Receptors Study
Columbia University
2015-2024
University of Iowa
2024
University of California, Los Angeles
2024
Brain (Germany)
2021-2022
The Francis Crick Institute
2020-2021
The Honourable Society of Lincoln's Inn
2014
Cancer Research UK
2014
MRC Laboratory of Molecular Biology
2009
University of Leeds
1975
Significance The large superfamily of cadherins serve essential roles in cell–cell interactions and guidance. extracellular cadherin (EC) domains responsible for the biological functions are decorated with O-linked mannose glycans, but these O-glycans poorly understood. Here we describe an O-mannosylation pathway orchestrated by four homologous TMTC1–4 genes that is dedicated selectively to superfamily. Mutations TMTC3 gene cause cobblestone lissencephaly, demonstrating importance this type...
Stochastic cell-surface expression of α-, β-, and γ-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures ectodomain fragments comprising cell-cell recognition regions mouse γ-Pcdhs γA1, γA8, γB2, γB7 revealing trans-homodimers, C-terminal from γA4 which depict cis-interacting in monomeric form. Together these span the entire γ-Pcdh ectodomain. The trans-dimer reveal determinants...
Clustered protocadherins (Pcdhs) mediate numerous neural patterning functions, including neuronal self-recognition and non-self-discrimination to direct self-avoidance among vertebrate neurons. Individual neurons stochastically express a subset of Pcdh isoforms, which assemble form stochastic repertoire cis-dimers. We describe the structure PcdhγB7 cis-homodimer, includes membrane-proximal extracellular cadherin domains EC5 EC6. The is asymmetric with one molecule contributing interface...
The stochastic expression of fewer than 60 clustered protocadherin (cPcdh) isoforms provides diverse identities to individual vertebrate neurons and a molecular basis for self-/nonself-discrimination. cPcdhs form chains mediated by alternating
Highlights•Kinetics of RET autophosphorylation identify early and late sites•Evidence for a kinase domain cis-inhibitory tether is presented•Oncogenic subverts cis-inhibition perturbs the trajectory•Oncogenic overactive better trans-autophosphorylation substrateSummaryTo decipher molecular basis activation oncogenic deregulation, we defined temporal sequence by label-free quantitative mass spectrometry. Early sites map to regions flanking core, while within loop only form at later time...
The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. binds a cell surface bipartite ligand comprising GDNF family GFRα coreceptor, resulting transmembrane signaling. We present hybrid structural model, derived from electron microscopy (EM) low-angle X-ray scattering (SAXS) data, of the extracellular domain (RETECD), GDNF, GFRα1 ternary complex, defining basis for recognition. RETECD envelopes dimeric complex through composite...
Sidekick (Sdk) 1 and 2 are related immunoglobulin superfamily cell adhesion proteins required for appropriate synaptic connections between specific subtypes of retinal neurons. Sdks mediate cell-cell with homophilic specificity that underlies their neuronal targeting function. Here we report crystal structures Sdk1 Sdk2 ectodomain regions, revealing similar homodimers mediated by the four N-terminal domains (Ig1–4), arranged in a horseshoe conformation. These Ig1–4 horseshoes interact novel...
Abstract Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance1-4. Clustered protocadherins (Pcdh), comprising large family isoform-specific homophilic recognition molecules, play pivotal role in self-avoidance required for mammalian brain development5-7. The probabilistic expression different Pcdh isoforms confers unique identities upon neurons processes to discriminate between self non-self5,6,8. Whether this self-recognition...
RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize activate stimulating its cytoplasmic function. The principles for ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish revealing interdomain flexibility between CLD2 CLD3. Comparison with cryo-electron microscopy ligand-engaged...
Abstract The stochastic expression of fewer than 60 clustered protocadherin (cPcdh) isoforms provides diverse identities to individual vertebrate neurons and a molecular basis for self/non-self- discrimination. cPcdhs form chains mediated by alternating cis trans interactions between apposed membranes, which has been suggested signal self-recognition. Such mechanism requires that cPcdh dimers promiscuously generate recognition units, have precise specificity so isoform mismatches terminate...
The RET receptor tyrosine kinase is crucial for embryonic and adult development, with mutations in both the extracellular domains leading to several types of cancer. In order understand mechanisms activation more detail, we have investigated how interacts its bipartite ligand comprising a glial cell line derived neurotrophic factor (GDNF) family GDNF (GFRalpha). To visualise this interaction, reconstituted two vertebrate ternary complexes containing co-receptor determined pseudo-atomic model...