Ligand-induced Structural Changes of the CD44 Hyaluronan-binding Domain Revealed by NMR

Takeda, Mitsuhiro; Ogino, Shuichi; Umemoto, Ryo; Sakakura, Masayoshi; Kajiwara, Masahiro; Sugahara, Kazuki N.; Hayasaka, Haruko; Miyasaka, Masayuki; Terasawa, Hiroaki; Shimada, Ichio

doi:10.1074/jbc.m608425200

Cited by 58 publications

(104 citation statements)

References 29 publications

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“…After the first week, however, both proliferation rate and CD44 gene level decreased in the calcite-HA culture. Activation of the receptor by HA is achieved via precise spatial folding of the HA chains [47,48], and we hypothesize that at the calcite-HA interface, the HA chains adopt a spatially orientated molecular conformation that is necessary to activate the CD44 receptor, a hypothesis supported by our previous investigation [20].…”

Section: Gene Expressionsupporting

confidence: 59%

Calcite Biohybrids as Microenvironment for Stem Cells

2012

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Abstract:A new type of composite 3D biomaterial that provides extracellular cues that govern the differentiation processes of mesenchymal stem cells (MSCs) has been developed. In the present study, we evaluated the chondrogenecity of a biohybrid composed of a calcium carbonate scaffold in its calcite polymorph and hyaluronic acid (HA). The source of the calcite scaffolding is an exoskeleton of a sea barnacle Tetraclita rifotincta (T. rifotincta), Pilsbry (1916). The combination of a calcium carbonate-based bioactive scaffold with a natural polymeric hydrogel is designed to mimic the organic-mineral composite of developing bone by providing a fine-tuned microenvironment. The results indicate that the calcite-HA interface creates a suitable microenvironment for the chondrogenic differentiation of MSCs, and therefore, the biohybrid may provide a tool for tissue-engineered cartilage.

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Section: Gene Expressionsupporting

confidence: 59%

Calcite Biohybrids as Microenvironment for Stem Cells

2012

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“…1B) (19), whereas it becomes disordered in the partially disordered (PD) state upon ligand binding (Fig. 1C) (20). In addition, solution NMR analyses demonstrated that HABD exists in an equilibrium between the O and PD states in both the HA-unbound and HAbound states, with a transition rate of ∼500 ms, and that HA binding induces an equilibrium shift toward the PD state (21) (Fig.…”

Section: E7304-e7305mentioning

confidence: 91%

“…The HA-binding domain (HABD) of CD44 adopts two distinctive conformations representing the low-and high-affinity states for HA (19)(20)(21). HABD is composed of a conserved Link module and the N-and C-terminal extension segment (22).…”

Section: E7304-e7305mentioning

confidence: 99%

Mechanical force effect on the two-state equilibrium of the hyaluronan-binding domain of CD44 in cell rolling

Suzuki

Ogino

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The authors note that Fig. 4 and Fig. S4 appeared incorrectly. The corrected figures and their legends appear below. The SI has been corrected online.The authors also note that on page 1 of the supporting information, right column, second full paragraph, lines 5-13, "The starting structure was solvated in a 62 × 129 × 69-Å TIP3 water box (6) with 54 chloride ions to neutralize the system, resulting in 53,872 atoms. The system was minimized for three consecutive 500-conjugate gradient steps, during which the protein was first held fixed; next, only the heavy atoms of the protein were held fixed, and finally, all atoms were allowed to move. After the energy minimizations, the system was heated gradually from 0 K to 310 K over 52 ps, and the temperature was maintained using Langevin dynamics" should instead appear as "The starting structure was solvated in a 68 × 116 × 79-Å TIP3 water box (6) with 53 chloride ions to neutralize the system, resulting in 59,606 atoms. The system was minimized for two consecutive 500-conjugate gradient steps, during which the protein was first held fixed; next, only the heavy atoms of the protein were held fixed. After the energy minimizations, the system was heated gradually from 0 K to 310 K over 9.3 ps, and the temperature was maintained using Langevin dynamics. Subsequently, the system was equilibrated by 4 rounds, first the heavy atoms were held fixed, then only backbone atoms, then only Cα atoms, and finally all atoms were allowed to move." These errors do not affect the conclusions of the article.A B C Fig. 4. Steered molecular dynamics (SMD) simulation of CD44 HABD by pulling force. (A) Snapshots of the HABD-HA8 complex at 0 ns (Left) and 3.5 ns (Right) during the SMD simulation. In the SMD simulation, the Cα carbon of the C-terminal residue Ile173 (gray sphere) was pulled at 10 Å/ns in the indicated direction (arrow), whereas the C2 atom of the N-acetylglucosamine residue (green sphere) was kept fixed. In the snapshot after 3.5 ns in the SMD simulation, the C-terminal mechanosensitive latch was completely separated from the α1 helix. (B) The time course of the hydrogen bond donor-acceptor distances between HA NAG1177 and I100 (red) and E52 and Y166 (blue). (C) Schematic depiction of the mechanosensitive latch in the force-induced conformational change of CD44 HABD.

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“…Recent investigations showed that cellmatrix interaction via CD44 induces activation of the small GTPase Rac (42) and stimuli such as PMA and ionomycin activate a disintegrin and metalloproteinase (ADAM)17 and ADAM10 (43,44), respectively, which then results in the cleavage of the CD44 ectodomain (43,44) and lamellipodia formation of the CD44-expressing cells (44,45). In addition, it was shown that LMW-HA interaction with CD44 triggers structural changes in CD44, resulting in an increased susceptibility of the CD44 molecule to proteolytic cleavage by trypsin (46). Therefore, a similar scenario can be envisaged for LMW-CSE that it initiates intracellular signaling pathways that activate proteases that cleave CD44, which became structurally susceptible to proteolysis, and also promote tumor cell motility by activating small GTPases.…”

Section: Discussionmentioning

confidence: 99%

Chondroitin Sulfate E Fragments Enhance CD44 Cleavage and CD44-Dependent Motility in Tumor Cells

et al. 2008

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During tumor cell invasion, certain extracellular matrix (ECM) components such as hyaluronan (HA) are degraded into small oligosaccharides, which are detected in patients. We previously reported that such HA oligosaccharides induce the proteolytic cleavage of an ECM-binding molecule CD44 from tumor cells and promote tumor cell migration in a CD44-dependent manner. Here, we report that chondroitin sulfate E (CSE), another component of the tumor ECM, strongly enhances CD44 cleavage and tumor cell motility when degraded into oligosaccharides. CSE and its degradation products were detected in pancreatic ductal adenocarcinoma. In CD44-expressing pancreatic tumor cells, degraded forms of CSE but not intact CSE enhanced CD44 cleavage; enzymatic digestion of such low-molecular weight CSE (LMW-CSE) abrogated this enhancement. Among the LMW-CSE preparations examined, 3-kDa CSE most potently induced CD44 cleavage. Nuclear magnetic resonance analysis showed that the 3-kDa-CSE bound to CD44, and that blocking such binding abrogated the CD44 cleavage induction. LMW-CSE also induced prominent filopodia formation and cytoskeletal changes in tumor cells; these effects were also abrogated by blocking the LMW-CSE binding to CD44. Chemically synthesized CSE hexasaccharides also enhanced the CD44 cleavage and tumor cell motility in a CD44-dependent manner. We conclude that the degraded forms of CSE modulate cell adhesion and migration by interacting with tumor-cell CD44, suggesting that the degradation products of tumor-associated ECMs that interact with CD44 play a significant role in CD44-mediated tumor progression. [Cancer Res 2008;68(17):7191-9]

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Ligand-induced Structural Changes of the CD44 Hyaluronan-binding Domain Revealed by NMR

Cited by 58 publications

References 29 publications

Calcite Biohybrids as Microenvironment for Stem Cells

Calcite Biohybrids as Microenvironment for Stem Cells

Mechanical force effect on the two-state equilibrium of the hyaluronan-binding domain of CD44 in cell rolling

Chondroitin Sulfate E Fragments Enhance CD44 Cleavage and CD44-Dependent Motility in Tumor Cells

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