RSS

PDB:2yad

Protein Name

BRICHOS domain from lung surfactant protein C proprotein (proSP-C)

Species

Homo sapiens

Biological Context

Surfactant protein C (SP-C), PDBID 1spf, is expressed in alveolar type II cells and is essential for lung function and the formation of a surface confined reservoir at the alveolar interface. The precursor of SP-C, proSP-C, contains the BRICHOS domain. The BRICHOS domain has been linked to major diseases such as familial British and Danish dementia, chondrosarcoma, stomach cancer and respiratory distress syndrome. It is believed that the proSP-C BRICHOS domain acts as a chaperone that targets the SP-C region of proSP-C and prevents its aggregation while assisting its safe membrane insertion as a transmembrane helix. Mutations in the BRICHOS domain of proSP-C can lead to misfolding, abnormal trafficking and processing of the proprotein.


Figure 1: Biosynthetic pathway of SP-C (Beers et al).

Structure Description

2yad2yad_x2yad_y

ProSP-C consists of four regions: a short N-terminal section, a transmembrane region which is secreted into the alveoli (main part of mature SP-C), a linker region and the BRICHOS domain. The majority of the proprotein consists of the BRICHOS domain (figure 2). The BRICHOS domain consists of two α-helices and five β-strands in a fold which previously has not been seen before and therefore no structural homologs are present in the PDB. The two α-helices enclose a central five-stranded β-sheet of which the four consecutive β-strands (β1-β4) form an anti-parallel β-sheet while the C-terminal β-strand β5 is parallel to β4. The two α-helices of which each diagonally stretch across a side of the β-sheet are amphiphilic. The hydrophobic side packs against the β-sheet to contribute to the hydrophobic core, while the polar side is either solvent accessible in the case of α1 or is buried in the interface between subunits (figure 3) in case of α2. The strictly conserved disulphide bridge between C121 and C189 which links β4 and α2 might be important for stability, while the in loop regions conserved Glycine and Proline residues may be important for the fold and for dynamical properties of the domain.


Figure 2: A: sequence of proSP-C. B: secondary structure of the BRICHOS domain (2yad).


Figure 3: Trimer formation of the BRICHOS domain.

References

Source

  1. Willander H, Askarieh G, Landreh M, Westermark P, Nordling K, Keränen H, Hermansson E, Hamvas A, Nogee LM, Bergman T, Saenz A, Casals C, Aqvist J, Jörnvall H, Berglund H, Presto J, Knight SD, Johansson J; "High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C."; Proc Natl Acad Sci U.S.A.; (2012) 109:2325-2329 PubMed:22308375.

Others

Author: Gert-Jan Bekker


Japanese version:PDB:2ic8