title: The metastasis-associated extracellular matrix protein osteopontin forms transient structure in ligand interaction sites.
abstract: Osteopontin (OPN) is an acidic hydrophilic glycophosphoprotein that was first identified as a major sialoprotein in bones. It functions as a cell attachment protein displaying a RGD cell adhesion sequence and as a cytokine that signals through integrin and CD44 cell adhesion molecules. OPN is also implicated in human tumor progression and cell invasion. OPN has intrinsic transforming activity, and elevated OPN levels promote metastasis. OPN gene expression is also strongly activated in avian fibroblasts simultaneously transformed by the v-myc and v-mil(raf) oncogenes. Here we have investigated the solution structure of a 220-amino acid recombinant OPN protein by an integrated structural biology approach employing bioinformatic sequence analysis, multidimensional nuclear magnetic resonance spectroscopy, synchrotron radiation circular dichroism spectroscopy, and small-angle X-ray scattering. These studies suggest that OPN is an intrinsically unstructured protein in solution. Although OPN does not fold into a single defined structure, its conformational flexibility significantly deviates from random coil-like behavior. OPN comprises distinct local secondary structure elements with reduced conformational flexibility and substantially populates a compact subspace displaying distinct tertiary contacts. These compacted regions of OPN encompass the binding sites for α(V)β(III) integrin and heparin. The conformational flexibility combined with the modular architecture of OPN may represent an important structural prerequisite for its functional diversity.
authors: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter Campus 5, A-1030 Vienna, Austria.
authors: Gerald
authors: G
authors: Platzer
authors: Andreas
authors: A
authors: Schedlbauer
authors: Angela
authors: A
authors: Chemelli
authors: Przemyslaw
authors: P
authors: Ozdowy
authors: Nicolas
authors: N
authors: Coudevylle
authors: Renate
authors: R
authors: Auer
authors: Georg
authors: G
authors: Kontaxis
authors: Markus
authors: M
authors: Hartl
authors: Andrew J
authors: AJ
authors: Miles
authors: B A
authors: BA
authors: Wallace
authors: Otto
authors: O
authors: Glatter
authors: Klaus
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authors: Bister
authors: Robert
authors: R
authors: Konrat