Differential regulation of elastic fiber formation by fibulin-4 and -5.
Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1, thereby revealing how they differentially regulate assembly. Strong binding between fibulin-4 and lysyl oxidase enhanced the interaction of fibulin-4 with tropoelastin, forming ternary complexes that may direct elastin cross-linking. In contrast, fibulin-5 did not bind lysyl oxidase strongly but bound tropoelastin in terminal and central regions and could concurrently bind fibulin-4. Both fibulins differentially bound N-terminal fibrillin-1, which strongly inhibited their binding to lysyl oxidase and tropoelastin. Knockdown experiments revealed that fibulin-5 controlled elastin deposition on microfibrils, although fibulin-4 can also bind fibrillin-1. These experiments provide a molecular account of the distinct roles of fibulin-4 and -5 in elastic fiber assembly and how they act in concert to chaperone cross-linked elastin onto microfibrils.
Choudhury
Rawshan
R
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
McGovern
Amanda
A
Ridley
Caroline
C
Cain
Stuart A
SA
Baldwin
Andrew
A
Wang
Ming-Chuan
MC
Guo
Chun
C
Mironov
Aleksandr
A
Drymoussi
Zoe
Z
Trump
Dorothy
D
Shuttleworth
Adrian
A
Baldock
Clair
C
Kielty
Cay M
CM
D002460:Cell Line; D004547:Elastic Tissue / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D000071838:Fibrillin-1; D000071837:Fibrillins; D055785:Gene Knockdown Techniques; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D020836:Protein Structure, Quaternary / Q000502:physiology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D014333:Tropoelastin / Q000235:genetics / Q000378:metabolism*; D054392:Adipokines
D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D008249:Protein-Lysine 6-Oxidase; D014333:Tropoelastin; C403672:EFEMP2 protein, human; C492373:FBLN5 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines