Abilities of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue

Abstract

Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but to what extent the respective mechanisms...

Amyloid inhibition by molecular chaperones in vitro can be translated to Alzheimer's pathology in vivo

“…BRICHOS mainly inhibits secondary nucleation events, preventing the generation of oligomers (here the Bri2 BRICHOS monomer is displayed). 1,3,4 DNAJB6 was found to bind Aβ oligomers 5 , causing a predominate reduction of primary nucleation 6,7 (the shown structure represents a monomeric subunit of the DNAJB6 oligomer). In contrast, clusterin rather specifically prevents fibril-end elongation 11 (here a monomeric subunit of clusterin is visualized).…”

OAF: a new member of the BRICHOS family

“…Other mature polypeptides of the BRICHOS family form amyloid-like structures ( Chen et al , 2022 ; Hedlund et al , 2009 ; Knight et al , 2013 ; Willander et al , 2011 ). To investigate this for OAF, we applied a machine learning approach, AMYPred-FRL, to its wild-type sequence ( Charoenkwan et al.…”

“…S3); (iv) a predicted disulphide bridge between a-helix 2 and b-strand 4, whose conserved cysteines have been involved in a homopolymerization mechanism in reducing conditions, key for the ATPindependent chaperone function of these domains (Leppert et al, 2022); and (v) a highly conserved aspartic acid (Asp74) located at the end of b-strand 2 (Supplementary Figs S2 and S3). This residue has been recently implicated in a pH-dependent regulatory mechanism of the BRICHOS domain's chaperone activity (Chen et al, 2022). It is also expected to have a key functional relevance in BRICHOS domains because its mutation in proSP-C causes interstitial lung disease (Pobre-Piza et al, 2022;Willander et al, 2012).…”

“…For most, their precursors consist of three parts: an N-terminal transmembrane region, part of either a signal peptide for secretion or a signal-anchor for type II membrane proteins, followed by a long BRICHOS domain and a C-terminal shorter mature polypeptide generated by proteolytic cleavage. BRICHOS domain-containing proteins have been characterized as pre-pro-proteins, which once secreted, undergo proteolytic processing, usually by proprotein convertases, releasing their mature form ( Chen et al , 2022 ; Hedlund et al , 2009 ; Knight et al , 2013 ; Sanchez-Pulido et al , 2002 ; Willander et al , 2011 ). Furin-cleavage of the transmembrane protein BRI2, for example, yields a 23 amino acid polypeptide that may then be released from the precursor molecule.…”

“…The mature forms of BRICHOS proteins thus have a natural propensity to aggregate, including into amyloid-like fibrils. To prevent this, BRICHOS domains have evolved intramolecular chaperone functions, transporting their amyloidogenic cargo to appropriate cellular locations where their proteins' mature polypeptides are released following proteolytic cleavage ( Chen et al , 2022 ; Gharibyan et al , 2022 ; Johansson et al , 2006 ; Knight et al , 2013 ; Landreh et al , 2015 ; Sanchez-Pulido et al , 2002 ; Willander et al , 2011 ).…”