ECM1 interacts with fibulin-3 and the beta 3 chain of laminin 332 through its serum albumin subdomain-like 2 domain |
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Authors: | S. Sercu A.M. Lambeir E. Steenackers A. El Ghalbzouri K. Geentjens T. Sasaki N. Oyama J. Merregaert |
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Affiliation: | 1. Laboratory of Molecular Biotechnology, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium;2. Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Wilrijk, Belgium;3. Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands;4. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, USA;5. Department of Dermatology, Fukushima Medical University School of Medicine, 1-Hikarigaoka, Fukushima 960-1295, Japan |
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Abstract: | The extracellular matrix protein 1 (ECM1) is an 85 kDa secreted glycoprotein, comprising four variants and playing a pivotal role in endochondral bone formation, angiogenesis, and tumour biology. A computational model for the three-dimensional structure of ECM1a was determined to identify the potential and/or concealed region(s) for binding with candidate partners in human skin. Multiple alignments for the secondary structure of ECM1a and b revealed similarity with serum albumin. The N-terminal domain of ECM1a consists mainly of α-helices (αD1), while the remaining three domains, namely serum albumin subdomain-like (SASDL) domains 2-4, were topologically comparable with the subdomain of the third serum albumin domain. Yeast-two-hybrid screening of a human foreskin cDNA library using both full-length ECM1a and the hot spot region for ECM1 gene mutations in lipoid proteinosis, an autosomal recessive genodermatosis (complete SASDL2 and the linker to SASDL3: aa177–aa361), as bait, isolated seven extracellular proteins. The site-specific interaction of ECM1a with two of these candidate binders, laminin 332 beta-3 chain and fibulin-3, was confirmed by in vitro and in vivo co-immunoprecipitation experiments. Immunohistologically both binders co-localized with ECM1 in human skin. Together, ECM1 is a multifunctional binding core and/or a scaffolding protein interacting with a variety of extracellular and structural proteins, contributing to the maintenance of skin integrity and homeostasis. Hence, disruption of the ECM1 function may cause the failure of multi-communication among the surrounding skin interstitial molecules, as seen in lipoid proteinosis pathology. |
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