Domain 1 of Mucosal Addressin Cell Adhesion Molecule Has an I1-set Fold and a Flexible Integrin-binding Loop

Yu, Yamei; Zhu, Jinghua; Huang, Po-Ssu; Wang, Jia-Huai; Pullen, Nick; Springer, Timothy A.

doi:10.1074/jbc.m112.413153

Cited by 8 publications

(6 citation statements)

References 44 publications

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“…The most ideal target(s) are cell membrane-bound proteins. Although Madcam1 was reported to bind integrin α4β7 and mediate lymphocyte adhesion to vascular surfaces [ 35 ], no direct evidence has indicated that Madcam1 is localized to the membrane. In HCC cells, we found that Madcam1 was primarily located in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells

Wang

Tang

et al. 2015

Oncotarget

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Doxorubicin (Doxo) is one of the most widely used chemotherapeutic drugs for patients with hepatocellular carcinoma (HCC). Doxo is a DNA intercalating drug that inhibits topoisomerase II. Thereby Doxo has the ability to block DNA replication and induce apoptosis. However, the other targets and mechanisms through which Doxo induces apoptosis to treat HCC still remain unknown. Here, we identified Mucosal vascular addressin cell adhesion molecule 1 (Madcam1) as a potential Doxo target because Madcam1 overexpression suppressed, while Madcam1 depletion stimulated Doxo-induced apoptosis. Furthermore, we first revealed that Doxo can induce apoptosis by blocking protein translation initiation. In contrast, Madcam1 activated protein translation through an opposite mechanism. We also found de-phosphorylation of AKT may be an important pro-apoptotic event that is triggered by Doxo-induced Madcam1 down-regulation. Finally, we revealed that Madcam1 promoted increased AKT phosphorylation, which is essential for maintaining the sensitivity of HCC cells to Doxo treatment. Taken together, we uncovered a potential mechanism for Doxo-induced apoptosis in HCC treatment through targeting Madcam1 and AKT and blocking protein translation initiation.

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Section: Discussionmentioning

confidence: 99%

Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells

Wang

Tang

et al. 2015

Oncotarget

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“…Data were reduced in HKL-2000 55 . The DH727.2-ZAM18 peptide structure was phased by molecular replacement in PHENIX 56 using as the search model the Fab fragment of an antibody to Madcam-1 Dld2 as selected by high sequence identity 57 . Likewise, the DH753-ZAM18 structure was phased using a composite search model generated from the Fab fragment of the HIV antibody 10E8 germline heavy chain 58 with the HIV antibody DH501 light chain 24 .…”

Section: Methodsmentioning

confidence: 99%

Difficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations

et al. 2019

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The HIV-1 envelope (Env) is the target for neutralizing antibodies and exists on the surface of virions in open or closed conformations. Difficult-to-neutralize viruses (tier 2) express Env in a closed conformation antigenic for broadly neutralizing antibodies (bnAbs) but not for third variable region (V3) antibodies. Here we show that select V3 macaque antibodies elicited by Env vaccination can neutralize 26% of otherwise tier 2 HIV-1 isolates in standardized virus panels. The V3 antibodies only bound to Env in its open conformation. Thus, Envs on tier 2 viruses sample a state where the V3 loop is not in its closed conformation position. Envelope second variable region length, glycosylation sites and V3 amino acids were signatures of neutralization sensitivity. This study determined that open conformations of Env with V3 exposed are present on a subset of otherwise neutralization-resistant virions, therefore neutralization of tier 2 HIV-1 does not always indicate bnAb induction.

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“…These two loops are responsible for the interaction between MAdCAM-1 and α4β7 ( Sun et al, 2011 ). Furthermore, a shift in D1 topology from the I2-set to I1-set was demonstrated by new crystals of MAdCAM-1 and two different Fabs, inducing a switch of integrin-binding loop from CC’ to CD ( Yu et al, 2013 ). The different conformations seen in crystal structures suggest that the integrin-binding loop of MAdCAM-1 is inherently flexible, which may explain why MAdCAM-1 could mediate both rolling and firm adhesion by binding to integrin α4β7 in different conformational states.…”

Section: Discussionmentioning

confidence: 96%

Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4β7-Mediated Cell Adhesion Through Electrostatic Repulsion

Yuan

Yang

et al. 2020

Front. Cell Dev. Biol.

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The homing of lymphocytes from blood to gut-associated lymphoid tissue is regulated by interaction between integrin α4β7 with mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) expressed on the endothelium of high endothelial venules (HEVs). However, the molecular basis of mucin-like domain, a specific structure of MAdCAM-1 regulating integrin α4β7-mediated cell adhesion remains obscure. In this study, we used heparan sulfate (HS), which is a highly acidic linear polysaccharide with a highly variable structure, to mimic the negative charges of the extracellular microenvironment and detected the adhesive behaviors of integrin α4β7 expressing 293T cells to immobilized MAdCAM-1 in vitro. The results showed that HS on the surface significantly promoted integrin α4β7-mediated cell adhesion, decreased the percentage of cells firmly bound and increased the rolling velocities at high wall shear stresses, which was dependent on the mucin-like domain of MAdCAM-1. Moreover, breaking the negative charges of the extracellular microenvironment of CHO-K1 cells expressing MAdCAM-1 with sialidase inhibited cell adhesion and rolling velocity of 293T cells. Mechanistically, electrostatic repulsion between mucin-like domain and negative charges of the extracellular microenvironment led to a more upright conformation of MAdCAM-1, which facilitates integrin α4β7-mediated cell adhesion. Our findings elucidated the important role of the mucin-like domain in regulating integrin α4β7-mediated cell adhesion, which could be applied to modulate lymphocyte homing to lymphoid tissues or inflammatory sites.

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Domain 1 of Mucosal Addressin Cell Adhesion Molecule Has an I1-set Fold and a Flexible Integrin-binding Loop

Cited by 8 publications

References 44 publications

Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells

Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells

Difficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations

Mucin-Like Domain of Mucosal Addressin Cell Adhesion Molecule-1 Facilitates Integrin α4β7-Mediated Cell Adhesion Through Electrostatic Repulsion

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