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Indirect role of Ca2+ in the assembly of extracellular matrix proteins.

ABSTRACT: We have investigated through molecular dynamics the binding properties at the interface between the C-type lectin subdomain (CLD) of aggrecan and the fibronectin type III domains ((4-5)FnIII) of tenasin, in particular the mechanistically unknown, but essential role of Ca(2+) in the binding. The binding between the CLD and (4-5)FnIII is critical in cross-linking aggrecan, hyaluronan, and tenascin to form extended protein networks found in tissues such as cartilage. None of the structurally resolved Ca(2+) ions in the complex of the CLD and (4-5)FnIII is directly bridging the two proteins. However, one of the Ca(2+) ions (Ca2) is found to play the role of maintaining the structure of the L4 loop at the CLD binding surface, thus facilitating a high affinity binding between the CLD and (4-5)FnIII. Removal of this Ca(2+) ion causes a drastic structural change in the L4 loop, which presumably hinders the binding of the CLD to the (4-5)FnIII. The other bound Ca(2+) ions (Ca1 and Ca3) have no significant effect on the structure of the CLD binding surface, and thus are not expected to affect the binding. Our results might also suggest that the role of Ca2 in maintaining the structure of the L4 loop is most important during the binding process. Once the complex is formed, the dependence of the complex on the structuring role of Ca2 is reduced. In response to tensile force, the CLD and (4-5)FnIII separate by breaking first the electrostatic interactions at the interface, followed by the hydrophobic ones. The sequence of the unbinding events and the maximum force required to separate the two proteins are independent of the presence of the Ca(2+) ions, underlying the indirect role of Ca(2+) in the binding.

SUBMITTER: Diao J

PROVIDER: S-EPMC2426659 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Indirect role of Ca2+ in the assembly of extracellular matrix proteins.

Diao Jiankuai J Tajkhorshid Emad E

Biophysical journal 20080321 1

We have investigated through molecular dynamics the binding properties at the interface between the C-type lectin subdomain (CLD) of aggrecan and the fibronectin type III domains ((4-5)FnIII) of tenasin, in particular the mechanistically unknown, but essential role of Ca(2+) in the binding. The binding between the CLD and (4-5)FnIII is critical in cross-linking aggrecan, hyaluronan, and tenascin to form extended protein networks found in tissues such as cartilage. None of the structurally resolv ...[more]

PMID: 18359797

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Project description:Interactions between cancer cells and the surrounding microenvironment are crucial determinants of cancer progression. During this process, bi-directional communication among tumor cells and cancer associated fibroblasts (CAF) regulate extracellular matrix (ECM) deposition and remodeling. As a result of this dynamic process, soluble ECM proteins can be released into the bloodstream and may represent novel circulating biomarkers useful for cancer diagnosis. The aim of the present study was to measure the levels of three circulating ECM related proteins (COL11A1, COL10A1 and SPARC) in plasma samples of lung cancer patients and in healthy heavy-smokers controls and test whether such measurements have diagnostic or prognostic value.Gene expression profiling of lung fibroblasts isolated from paired normal and cancer tissue of NSCLC patients was performed by gene expression microarrays. The prioritization of the candidates for the study of circulating proteins in plasma was based on the most differentially expressed genes in cancer associated fibroblasts. Soluble ECM proteins were assessed by western blot in the conditioned medium of lung fibroblasts and by ELISA assays in plasma samples.Plasma samples from lung cancer patients and healthy heavy-smokers controls were tested for levels of COL11A1 and COL10A1 (n?=?57 each) and SPARC (n?=?90 each). Higher plasma levels of COL10A1 were detected in patients (p???0.001), a difference that was driven specifically by females (p?<?0.001). No difference in COL11A1 levels between patients and controls was found. SPARC levels were also higher in plasma patients than controls (p?<?0.001) with good performance in discriminating the two groups (AUC?=?0.744). No significant association was observed between plasma proteins levels and clinicopathological features or survival.Soluble factors related to proficient tumor-stroma cross-talk are detectable in plasma of primary lung cancer patients and may represent a valuable complementary diagnostic tool to discriminate lung cancer patients from healthy heavy-smokers individuals as shown for the SPARC protein.

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Indirect role of Ca2+ in the assembly of extracellular matrix proteins.

Publications

Indirect role of Ca2+ in the assembly of extracellular matrix proteins.

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