Medin: An integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid
- Bo Häggqvist*,
- Jan Näslund†,
- Knut Sletten‡,
- Gunilla T. Westermark,
- Gerd Mucchiano*,
- Lars O. Tjernberg†,
- Christer Nordstedt†,
- Ulla Engström¶, and
- Per Westermark‖,**
- Divisions of *Molecular and Immunological Pathology and Cell Biology, Linköping University, S-581 85 Linköping, Sweden; †Laboratory of Biochemistry and Molecular Pharmacology, Department of Clinical Neuroscience, Karolinska Hospital, S-171 76 Stockholm, Sweden; ‡Department of Biochemistry and Biotechnology Center, University of Oslo, N-0316 Oslo, Norway; ¶Ludwig Institute for Cancer Research, Uppsala Branch, S-751 24 Uppsala, Sweden; and ‖Department of Genetics and Pathology, Uppsala University, S-751 85 Uppsala, Sweden
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Communicated by Donald F. Steiner, The University of Chicago, Chicago, IL (received for review April 7, 1999)
Abstract
Aortic medial amyloid is a form of localized amyloid that occurs in virtually all individuals older than 60 years. The importance and impact of the amyloid deposits are unknown. In this study we have purified a 5.5-kDa aortic medial amyloid component, by size-exclusion chromatography and RP-HPLC, from three individuals, and we have shown by amino acid sequence analysis that the amyloid is derived from an integral proteolytic fragment of lactadherin. Lactadherin is a 364-aa glycoprotein, previously known to be expressed by mammary epithelial cells as a cell surface protein and secreted as part of the milk fat globule membrane. The multidomain protein has a C-terminal domain showing homology to blood coagulation factors V and VIII. We found that the main constituent of aortic medial amyloid is a 50-aa-long peptide, here called medin, that is positioned within the coagulation factor-like domain of lactadherin. Our result is supported by the specific labeling of aortic medial amyloid in light and electron microscopy with two rabbit antisera raised against two synthetic peptides corresponding to different parts of medin. By using in situ hybridization we have shown that lactadherin is expressed by aortic medial smooth muscle cells. Furthermore, one of the synthetic peptides forms amyloid-like fibrils in vitro. Lactadherin was not previously known to be an amyloid precursor protein or to be expressed in aortic tissue. The structure of lactadherin may implicate an important regulatory function in the aorta.
