The University of Osaka · Medicine
Professor Junichi Takagi's research lab specializes in structural biology and molecular mechanisms underlying integrin function, with a focus on how conformational changes regulate ligand binding and cell adhesion. The lab investigates the structural basis of integrin activation, particularly in immune and platelet cells, using advanced techniques such as cryo-electron microscopy, X-ray crystallography, and NMR. A key research direction involves understanding the role of sorting receptors like SORLA in neurodegenerative diseases, especially Alzheimer’s disease, where they modulate amyloid-β production. The lab also explores the molecular determinants of integrin ligand specificity and signaling through domain-swapping and mutagenesis studies.
Figures are computed from collected data and may differ slightly.
Among adhesion receptor families, integrins are particularly important in biological processes that require rapid modulation of adhesion and de-adhesion. Activation on a timescale of < 1 s of beta2 integrins on leukocytes and beta3 integrins on platelets enables deposition of these cells at sites of inflammation or vessel wall injury. Recent crystal, nuclear magnetic resonance (NMR), and electron microscope (EM) structures of integrins and their domains lead to a unifying mechanism of activation
SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-β (Aβ) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse
Since the discovery of the RGD sequence motif as the essential cell attachment site in Fn (fibronectin), RGD-dependent ligand recognition by integrins has been the major focus of many integrin researches. Although many integrins recognize RGD-containing ligands, it is believed that residues outside the RGD motif provide specificity as well as high affinity for each integrin-ligand pair. These 'secondary' sites are generally assumed to interact directly with the alpha subunit of integrin, whereas
Integrin α<sub>5</sub>β<sub>1</sub> is a major fibronectin receptor critical for cell migration. Upon complex formation, fibronectin and α<sub>5</sub>β<sub>1</sub> undergo conformational changes. While this is key for cell-tissue connections, its mechanism is unknown. Here, we report cryo-electron microscopy structures of native human α<sub>5</sub>β<sub>1</sub> with fibronectin to 3.1-angstrom resolution, and in its resting state to 4.6-angstrom resolution. The α<sub>5</sub>β<sub>1</sub>-fibrone
The affinity of the extracellular domain of integrins for ligand is regulated by conformational changes signaled from the cytoplasm. Alternative types of conformational movement in the ligand-binding headpiece have been proposed. In one study, electron micrograph image averages of the headpiece of integrin aV beta 3 show two different conformations. The open conformation of the headpiece is present when a ligand mimetic peptide is bound and differs from the closed conformation in the presence of
Integrins mediate signal transduction through interaction with multiple cellular or extracellular matrix ligands. Integrin alphavbeta3 recognizes fibrinogen, von Willebrand factor, and vitronectin, while alphavbeta1 does not. We studied the mechanisms for defining ligand specificity of these integrins by swapping the highly diverse sequences in the I domain-like structure of the beta1 and beta3 subunits. When the sequence CTSEQNC (residues 187-193) of beta1 is replaced with the corresponding CYD
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