Details

Autor(en) / Beteiligte

• Kim, Bitnarae
• Kim, Seungsu
• Jin, Mi Sun

Titel

Crystal structure of the human glial fibrillary acidic protein 1B domain

Ist Teil von

• Biochemical and biophysical research communications, 2018-09, Vol.503 (4), p.2899-2905

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• Glial fibrillary acidic protein (GFAP) is a homopolymeric type III intermediate filament (IF) that plays essential roles in cell migration, mitosis, development, and signaling in astrocytes and a specific type of glial cells. Its overexpression and genetic mutations lead to abnormal IF networks and accumulation of Rosenthal fibers, which results in the fatal neurodegenerative disorder Alexander disease. Herein, we present the first crystal structure of human GFAP spanning the central coiled-coil 1B domain at 2.5 Å resolution. The domain forms a tetramer comprising two equivalent parallel coiled-coil dimers that pack together in an antiparallel manner. Its assembly is stabilized by extensive networks of intermolecular hydrogen bonds, salt bridges, and hydrophobic interactions. Furthermore, mapping of the GFAP mutations associated with Alexander disease reveals that most involve residues buried in the core of the interface, and are likely to disrupt the intermolecular interactions and/or introduce steric clashes, thereby decreasing GFAP solubility and promoting aggregation. Based on our structural analysis and previous biochemical studies, we propose that GFAP assembles in the A11 mode in which coiled-coil 1B dimers lie in close axial proximity in an antiparallel fashion to provide a stable tetrameric platform for the organization of the GFAP filament. •The first crystal structure of the human GFAP 1B domain was determined.•Two parallel coiled-coils pack together lengthwise in an antiparallel configuration.•H-bonds, salt bridges, and hydrophobic interactions stabilize the homotetramer.•Alexander disease mutations disrupt the interactions and the GFAP filament network.