期刊
BIOCHEMICAL JOURNAL
卷 402, 期 -, 页码 63-70出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20061145
关键词
elastic fibre assembly; elastin; microfibril; supravalvular aortic stenosis (SVAS); tropoelastin
资金
- NHLBI NIH HHS [HL073703, R01 HL073703] Funding Source: Medline
Naturally occurring mutations are useful in identifying domains that are important for protein function. We studied a mutation in the elastin gene, 800-3G > C, a common disease allele for SVAS (supravalvular aortic stenosis). We showed in primary skin fibroblasts from two different SVAS families that this mutation causes skipping of exons 16-17 and results in a stable mRNA. Tropoelastin lacking domains 16-17 (Delta 16-17) was synthesized efficiently and secreted by transfected retinal pigment epithelium cells, but showed the deficient deposition into the extracellular matrix compared with normal as demonstrated by immunofluorescent staining and desmosine assays. Solid-phase binding assays indicated normal molecular interaction of Delta 16-17 with fibrillin-1 and fibulin-5. However, self-association of Delta 16-17 was diminished as shown by an elevated coacervation temperature. Moreover, negative staining electron microscopy confirmed that Delta 16-17 was deficient in forming fibrillar polymers. Domain 16 has high homology with domain 30, which can form a beta-sheet structure facilitating fibre formation. Taken together, we conclude that domains 16-17 are important for self-association of tropoelastin and elastic fibre formation. This study is the first to discover that domains of elastin play an essential role in elastic fibre formation by facilitating homotypic interactions.
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