Structural and thermodynamic characterization of the self-adhesive properties of human P-cadherin

Kudo, Shota; Caaveiro, José M. M.; Miyafusa, Takamitsu; Goda, Shuichiro; Ishii, Keisuke; Matsuura, Tadashi; Sudou, Yukio; Kodama, Tatsuhiko; Hamakubo, Takao; Tsumoto, Kouhei

doi:10.1039/c2mb25161b

Cited by 9 publications

(16 citation statements)

References 23 publications

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“…1a)15161718. In particular, the mechanism of cell adhesion by human P-cadherin has also been elucidated at the molecular and cellular levels192021. In these studies we have showed that the so-called strand-swap dimer is the active cell adhesive species, in agreement with what has been reported for other classical cadherins.…”

supporting

confidence: 84%

Disruption of cell adhesion by an antibody targeting the cell-adhesive intermediate (X-dimer) of human P-cadherin

Kudo

Caaveiro

Nagatoishi

et al. 2017

Sci Rep

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Human P-cadherin is a cell adhesion protein of the family of classical cadherins, the overexpression of which is correlated with poor prognosis in various types of cancer. Antibodies inhibiting cell-cell adhesion mediated by P-cadherin show clear therapeutic effect, although the mechanistic basis explaining their effectiveness is still unclear. Based on structural, physicochemical, and functional analyses, we have elucidated the molecular mechanism of disruption of cell adhesion by antibodies targeting human P-cadherin. Herein we have studied three different antibodies, TSP5, TSP7, and TSP11, each recognizing a different epitope on the surface of the cell-adhesive domain (EC1). Although all these three antibodies recognized human P-cadherin with high affinity, only TSP7 disrupted cell adhesion. Notably, we demonstrated that TSP7 abolishes cell adhesion by disabling the so-called X-dimer (a kinetic adhesive intermediate), in addition to disrupting the strand-swap dimer (the final thermodynamic state). The inhibition of the X-dimer was crucial for the overall inhibitory effect, raising the therapeutic value of a kinetic intermediary not only for preventing, but also for reversing, cell adhesion mediated by a member of the classical cadherin family. These findings should help to design more innovative and effective therapeutic solutions targeting human P-cadherin.

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confidence: 84%

Disruption of cell adhesion by an antibody targeting the cell-adhesive intermediate (X-dimer) of human P-cadherin

Kudo

Caaveiro

Nagatoishi

et al. 2017

Sci Rep

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“…1 and Tables S2-3). Notably, Trp239 locates at the N-terminal end of LI-cadherin EC3 and because of that it has been suggested that this Trp residue might function as an adhesive element equivalent to that of the conserved residue Trp2 of EC1 of classical cadherins, playing a crucial role in the formation of strand swap-dimer (ss-dimer) (9, 10, 17–19). Considering the degree of sequence homology and that EC1-2 of classical cadherins is the element responsible for homodimerization, we hypothesized that EC1-2 and EC3-4 of LI-cadherin would be responsible for its dimerization.…”

Section: Resultsmentioning

confidence: 99%

“…The experimental procedure is described previously (56). All remaining data are contained within the article.…”

Section: Solution Structure Analysis Using Saxsmentioning

confidence: 99%

Dimerization mechanism and structural features of human LI-cadherin

Yui

Caaveiro

Kuroda

et al. 2020

Preprint

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LI-cadherin is a member of cadherin superfamily which is a Ca2+-dependent cell adhesion protein. Its expression is observed on various types of cells in the human body such as normal small intestine and colon cells, and gastric cancer cells. Because its expression is not observed on normal gastric cells, LI-cadherin is a promising target for gastric cancer imaging. However, since the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutics targeting this cadherin has been complicated. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin EC1-4 homodimer. The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between EC2 and EC3. We also show that LI-cadherin EC1-2 and EC3-4 have different characteristics to that of the EC1-2 domains of classical cadherins despite the sequence similarity among them. Various biochemical techniques, molecular dynamics (MD) simulations and small angle X-ray scattering (SAXS) were employed to elucidate the mechanism of homodimerization. We expect these findings will advance the generation of therapeutic molecules targeting LI-cadherin and to establish the specific role of LI-cadherin on cancer cells.

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“…Nonclassical T-cadherin, which lacks the Trp2-containing strand and is therefore unable to promote strand-swap dimer formation, has been found to dimerize at the Ca 2+ -binding site between the EC1 and EC2 domains, forming what is usually referred to as the X-dimer (Ciatto et al, 2010), a structural arrangement that is topologically identical to that found in E-cadherin mutants which are unable to form the strand-swap dimer (Harrison et al, 2010;Nagar et al, 1996;Pertz et al, 1999). Recently, the X-dimer of P-cadherin has also been identified and characterized by a combination of mutational, spectroscopic and thermodynamic approaches (Kudo et al, 2012(Kudo et al, , 2014. Like the strand-swap dimer, the X-dimer arrangement also provides adhesive force between cadherin molecules (Rakshit et al, 2012) and it is believed to be a crucial intermediate state in the full cadherin dimerization trajectory.…”

Section: Introductionmentioning

confidence: 99%

The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway

et al. 2015

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Cadherins are a large family of calcium-dependent proteins that mediate cellular adherens junction formation and tissue morphogenesis. To date, the most studied cadherins are those classified as classical, which are further divided into type I or type II depending on selected sequence features. Unlike other members of the classical cadherin family, a detailed structural characterization of P-cadherin has not yet been fully obtained. Here, the high-resolution crystal structure determination of the closed form of human P-cadherin EC1-EC2 is reported. The structure shows a novel, monomeric packing arrangement that provides a further snapshot in the yet-to-be-achieved complete description of the highly dynamic cadherin dimerization pathway. Moreover, this is the first multidomain cadherin fragment to be crystallized and structurally characterized in its closed conformation that does not carry any extra N-terminal residues before the naturally occurring aspartic acid at position 1. Finally, two clear alternate conformations are observed for the critical Trp2 residue, suggestive of a transient, metastable state. The P-cadherin structure and packing arrangement shown here provide new and valuable information towards the complete structural characterization of the still largely elusive cadherin dimerization pathway.

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Structural and thermodynamic characterization of the self-adhesive properties of human P-cadherin

Cited by 9 publications

References 23 publications

Disruption of cell adhesion by an antibody targeting the cell-adhesive intermediate (X-dimer) of human P-cadherin

Disruption of cell adhesion by an antibody targeting the cell-adhesive intermediate (X-dimer) of human P-cadherin

Dimerization mechanism and structural features of human LI-cadherin

The X-ray structure of human P-cadherin EC1-EC2 in a closed conformation provides insight into the type I cadherin dimerization pathway

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