The fibrillogenic L178H variant of apolipoprotein A-I forms helical fibrils.
Author
Summary, in English
A number of amyloidogenic variants of apolipoprotein A-I (apoA-I) have been discovered but most have not been analyzed. Previously, we showed that the G26R mutation of apoA-I leads to increased β-strand structure, increased N-terminal protease susceptibility and increased fibril formation after several days of incubation. In vivo, this and other variants mutated in the N-terminal domain (residues 26 to ~90) lead to renal and hepatic accumulation. In contrast, several mutations identified within residues 170 to 178 lead to cardiac, laryngeal, and cutaneous protein deposit. Here, we describe the structural changes in the fibrillogenic variant L178H. Like G26R, the initial structure of the protein exhibits altered tertiary conformation relative to WT protein along with decreased stability and an altered lipid binding profile. However, in contrast to G26R, L178H undergoes an increase in helical structure upon incubation at 37oC with a t1/2 of about 12 days. Upon prolonged incubation the L178H mutant forms fibrils of a diameter of 10 nm that ranges in length from 30 to 120 nm. JLR These results show that apoA-I, known for its dynamic properties, has the ability to form multiple fibrillar conformations, which may play a role in the tissue-specific deposition of the individual variants.
Department/s
Publishing year
2012
Language
English
Pages
390-398
Publication/Series
Journal of Lipid Research
Volume
53
Issue
3
Full text
Links
Document type
Journal article
Publisher
American Society for Biochemistry and Molecular Biology
Topic
- Endocrinology and Diabetes
- Cell and Molecular Biology
- Infectious Medicine
Status
Published
Research group
- Medical Protein Science
- Diabetes - Islet Patophysiology
ISBN/ISSN/Other
- ISSN: 1539-7262