Heparan sulfate regulates fibrillin-1 N- and C-terminal interactions.
Fibrillin-1 N- and C-terminal heparin binding sites have been characterized. An unprocessed monomeric N-terminal fragment (PF1) induced a very high heparin binding response, indicating heparin-mediated multimerization. Using PF1 deletion and short fragments, a heparin binding site was localized within the domain encoded by exon 7 after the first hybrid domain. Rodent embryonic fibroblasts adhered to PF1 and deletion fragments, and, when cells were plated on fibrillin-1 or fibronectin Arg-Gly-Asp cell-binding fragments, cells showed heparin-dependent spreading and focal contact formation in response to soluble PF1. Within domains encoded by exons 59-62 near the fibrillin-1 C terminus are novel conformation-dependent high affinity heparin and tropoelastin binding sites. Heparin disrupted tropoelastin binding but did not disrupt N- and C-terminal fibrillin-1 interactions. Thus, fibrillin-1 N-terminal interactions with heparin/heparan sulfate directly influence cell behavior, whereas C-terminal interactions with heparin/heparan sulfate regulate elastin deposition. These data highlight how heparin/heparan sulfate controls fibrillin-1 interactions.
Cain
Stuart A
SA
Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, United Kingdom.
Baldwin
Andrew K
AK
Mahalingam
Yashithra
Y
Raynal
Bertrand
B
Jowitt
Thomas A
TA
Shuttleworth
C Adrian
CA
Couchman
John R
JR
Kielty
Cay M
CM
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005091:Exons / Q000235:genetics; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006493:Heparin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010449:Peptide Mapping / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017384:Sequence Deletion / Q000502:physiology; D014333:Tropoelastin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D006493:Heparin; D006497:Heparan Sulfate; D008840:Microfilament Proteins; D014333:Tropoelastin; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse; C000605725:Fbn1 protein, rat