BRICHOS domain associated with lung fibrosis, dementia and cancer – a chaperone that prevents amyloid fibril formation?

Abstract

The BRICHOS domain was initially defined from sequence alignments of the Bri protein associated with familial dementia, chondromodulin associated with chondrosarcoma and surfactant protein C precursor (proSP-C) associated with respiratory distress syndrome and interstitial lung disease (ILD). Today BRICHOS has been found in 12 protein families. Mutations in the Bri2 and proSP-C genes result in familial dementia and ILD, respectively, and both these conditions are associated with amyloid formation. Amyloid is of great medical relevance as it is found in several major incurable diseases, like Alzheimer's and Parkinson's disease and diabetes mellitus. Work on recombinant BRICHOS domains and transfected cells indicate that BRICHOS is a chaperone domain that, during biosynthesis, binds to precursor protein regions with high b-sheet propensities, thereby preventing them from amyloid formation. Regions prone to form b-sheets are present in all BRICHOS-containing precursor proteins and are probably eventually released by proteolytic cleavage, generating different peptides with largely unknown bioactivities. Recombinant BRICHOS domains from Bri2 and proSP-C have been found to efficiently prevent SP-C, the amyloid b-peptide associated with Alzheimer's disease, and medin, found in aortic amyloid, from forming amyloid fibrils. The data collected so far on BRICHOS raise several interesting topics for further research: (a) amyloid formation is a potential threat for many more proteins than the ones recognized so far in amyloid diseases; (b) amyloid formation of widely different peptides involves intermediate(s) that are recognized by the BRICHOS domain, suggesting that they have distinct structural similarities; and (c) the BRICHOS domain might be harnessed in therapeutic strategies against amyloid diseases.

BRICHOS Domains Efficiently Delay Fibrillation of Amyloid β-Peptide

“…1). We have speculated that the BRICHOS domains bind to regions within their respective precursor proteins that show high propensity to form ␤-sheet structures, preventing them from aggregation during biosynthesis (43,62,63). The A␤ central hydrophobic segment flanked by charged residues ( 14 HHKLVFFAED 23 ) is suggested as a target for both BRICHOS proteins (34,38,43).…”

Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

“…The proSP-C BRICHOS domain displays antiamyloidogenic chaperone activity, and mutations in this domain lead to the accumulation of SP-C amyloid (33). The proSP-C BRICHOS domain hence may be a chaperone tailored to interact with a particularly amyloidogenic sequence (34,35). Other BRICHOS homologues possess similar chaperone activity (36,37).…”

4-Phenylbutyric Acid Treatment Rescues Trafficking and Processing of a Mutant Surfactant Protein–C

“…Mutant proSP-C, including SP-C L188Q , can form amyloid-like fibrils (15) related to the loss of chaperone activity of the Brichos domain (14,29) and subsequent transition of the a-helical transmembrane domain to a b-sheet structure (30,31). Artificial b-sheet proteins that form amyloid-like fibrils have been shown to sequester proteins required for critical cellular functions (32).…”