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Although homotypic and heterotypic fibrillin self-interactions are considered to provide critical initial steps, the detailed mechanisms for microfibril assembly are unknown. We show here that the C-terminal recombinant half of fibrillin-1 assembles into disulfide-bonded multimeric globular structures with peripheral arms and a dense core. These globules are similar to the beaded structures observed in microfibrils isolated from tissues. Only these C-terminal fibrillin-1 multimers interacted strongly with the fibrillin-1 N terminus, whereas the monomers showed very little self-interaction activity. The multimers strongly inhibited microfibril formation in cell culture, providing evidence that these recombinant assemblies can also interact with endogenous fibrillin-1. The C-terminal self-interaction site was fine-mapped to the last three calcium-binding EGF domains in fibrillin-1. These results suggest a new mechanism for microfibril formation where fibrillin-1 first oligomerizes via its C terminus before the partially or fully assembled bead-like structures can further interact with other beads via the fibrillin-1 N termini.<\/jats:p>","DOI":"10.1073\/pnas.0706335105","type":"journal-article","created":{"date-parts":[[2008,4,30]],"date-time":"2008-04-30T21:24:51Z","timestamp":1209590691000},"page":"6548-6553","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":76,"title":["Biogenesis of extracellular microfibrils: Multimerization of the fibrillin-1 C terminus into bead-like structures enables self-assembly"],"prefix":"10.1073","volume":"105","author":[{"given":"Dirk","family":"Hubmacher","sequence":"first","affiliation":[{"name":"*Faculty of Medicine, Department of Anatomy and Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehab 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and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,5,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(06)75004-9"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.039669"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.103.6.2499"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1017\/S146239940600007X"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1177\/44.12.8985131"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00092.2004"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/39.4.2005373"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.99.4.797"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/978-1-4419-9013-6_12","volume-title":"Marfan Syndrome: A Primer for Clinicians and 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