Universität zu Köln

Sasaki, Takako, Hanisch, Franz-Georg, Deutzmann, Rainer, Sakai, Lynn Y., Sakuma, Tetsushi ORCID: 0000-0003-0396-1563, Miyamoto, Tatsuo ORCID: 0000-0002-1097-0647, Yamamoto, Takashi ORCID: 0000-0002-6516-2903, Hannappel, Ewald, Chu, Mon-Li, Lanig, Harald ORCID: 0000-0003-1593-5557 and von der Mark, Klaus (2016). Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa. Matrix Biol., 56. S. 132 - 150. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 1569-1802

Full text not available from this repository.

Abstract

Fibulin-4 is a 60 kDa calcium binding glycoprotein that has an important role in development and integrity of extracellular matrices. It interacts with elastin, fibrillin-1 and collagen IV as well as with lysyl oxidases and is involved in elastogenesis and cross-link formation. To date, several mutations in the fibulin-4 gene (FBLN4/EFEMP2) are known in patients whose major symptoms are vascular deformities, aneurysm, cutis laxa, joint laxity, or arachnodactyly. The pathogenetic mechanisms how these mutations translate into the clinical phenotype are, however, poorly understood. In order to elucidate these mechanisms, we expressed fibulin-4 mutants recombinantly in HEK293 cells, purified the proteins in native forms and analyzed alterations in protein synthesis, secretion, matrix assembly, and interaction with other proteins in relation to wild type fibulin-4. Our studies show that different mutations affect these properties in multiple ways, resulting in fibulin-4 deficiency and/or impaired ability to form elastic fibers. The substitutions E126K and C267Y impaired secretion of the protein, but not mRNA synthesis. Furthermore, the E126K mutant showed less resistance to proteases, reduced binding to collagen IV and fibrillin-1, as well as to LTBP1s and LTBP4s. The A397T mutation introduced an extra O-glycosylation site and deleted binding to LTBP1s. We show that fibulin-4 binds stronger than fibulin-3 and -5 to LTBP1s, 3, and 4s, and to the lysyl oxidases LOX and LOXL1; the binding of fibulin-4 to the LOX propeptide was strongly reduced by the mutation E57K. These findings show that different mutations in the fibulin-4 gene result in different molecular defects affecting secretion rates, protein stability, LOX-induced cross-linking, or binding to other ECM components and molecules of the TGF-13 pathway, and thus illustrate the complex role of fibulin-4 in connective tissue assembly. (C) 2016 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sasaki, Takako UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanisch, Franz-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Deutzmann, Rainer UNSPECIFIED UNSPECIFIED UNSPECIFIED Sakai, Lynn Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sakuma, Tetsushi UNSPECIFIED orcid.org/0000-0003-0396-1563 UNSPECIFIED Miyamoto, Tatsuo UNSPECIFIED orcid.org/0000-0002-1097-0647 UNSPECIFIED Yamamoto, Takashi UNSPECIFIED orcid.org/0000-0002-6516-2903 UNSPECIFIED Hannappel, Ewald UNSPECIFIED UNSPECIFIED UNSPECIFIED Chu, Mon-Li UNSPECIFIED UNSPECIFIED UNSPECIFIED Lanig, Harald UNSPECIFIED orcid.org/0000-0003-1593-5557 UNSPECIFIED von der Mark, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-254957
DOI:	10.1016/j.matbio.2016.06.003
Journal or Publication Title:	Matrix Biol.
Volume:	56
Page Range:	S. 132 - 150
Date:	2016
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	1569-1802
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXTRACELLULAR-MATRIX PROTEINS; LYSYL-OXIDASE; ELASTIC FIBER; BIOCHEMICAL-CHARACTERIZATION; STRUCTURAL CHARACTERIZATION; ARTERIAL TORTUOSITY; TISSUE LOCALIZATION; AORTIC-ANEURYSM; MARFAN-SYNDROME; CROSS-LINKING Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25495