A new kid in the folding funnel: Molecular chaperone activities of the BRICHOS domain

Abstract

The BRICHOS protein superfamily is a diverse group of proteins associated with a wide variety of human diseases, including respiratory distress, COVID-19, dementia, and cancer. A key characteristic of these proteins-besides their BRICHOS domain present in the ER lumen/extracellular part-is that they harbor an aggregation-prone region, which the BRICHOS domain is proposed to chaperone during biosynthesis. All so far studied BRICHOS domains modulate the aggregation pathway of various amyloid-forming substrates, but not all of them can keep denaturing proteins in a folding-competent state, in a similar manner as small heat shock proteins. Current evidence suggests that the ability to interfere with the aggregation pathways of substrates with entirely different end-point structures is dictated by BRICHOS quaternary structure as well as specific surface motifs. This review aims to provide an overview of the BRICHOS protein family and a perspective of the diverse molecular chaperone-like functions of various BRICHOS domains in relation to their structure and conformational plasticity. Furthermore, we speculate about the physiological implication of the diverse molecular chaperone functions and discuss the possibility to use the BRICHOS domain as a blood-brain barrier permeable molecular chaperone treatment of protein aggregation disorders.

Keywords: Alzheimer disease treatment; amyloid; blood-brain barrier; molecular chaperone; protein misfolding.

FIGURE 1

Phylogeny of BRICHOS proproteins and their domain architecture. (a) Phyla of BRICHOS domain‐containing proteins. (b) Common architectures of BRICHOS proproteins with the transmembrane (TM), signal peptide (SP), BRICHOS domain, conserved disulfide, and amyloidogenic region indicated. (c) Neighbor‐joining consensus tree of human BRICHOS families, their architecture, and known disease association. Chondrosarcoma has been associated with CNMD and gastric cancer has been linked to GKN1 and GKN2, while mutations in Bri2 are linked to familial British and Danish dementias (FBD and FDD, respectively). The numerical branch labels correspond to the consensus support (%) and the scale bar refers to a phylogenetic distance of 0.5 substitutions per site. (d) Experimentally solved structure of proSP‐C BRICHOS (PDB 2yad) showing a central β‐sheet flanked by one α‐helix (cylinder) on each side. Face A is assigned as the surface of the central β‐sheet facing α‐helix 1. The conserved disulfide bridge and Asp amino acid residue are heightened in yellow and red, respectively. The dashed line indicates the missing region between the two helices.

FIGURE 2

Structure characteristics of all human BRICHOS domains. (a) Pairwise amino acid sequence identities (%) of the 10 human BRICHOS domains color‐coded from low (red) to high (blue) degrees of identities. (b) AF2 structure predictions of human BRICHOS domains from: ITM2A (also known as Bri1, residues 122–227), ITM2B (Bri2, residues 126–231), ITM2C (Bri3, residues 125–230), BRICD5 (residues 89–195), CNMD (residues 97–204), TNMD (residues 86–190), GKN1 (residues 61–166), GKN2 (residues 47–130), OAF (residues 29–130), and proSP‐C (residues 90–197). Bottom right panel shows the overlay of all models where the β‐sheet is colored gray, and the locations of the helices are indicated.

FIGURE 3

Native client binding of BRICHOS domains. AF2 predictions of (a) human proSP‐C BRICHOS (residues 60–197; gray and yellow) in complex with a poly‐Val peptide (red) (adopted from Osterlund et al. (2022)) and (b) Bri2 BRICHOS domain (gray and blue) and C‐terminal aggregation‐prone region (Bri23, red; residues 85–266). (c) Per‐residue confidence score (pLDDT) plots around the region connecting helix 1 and 2 in proSP‐C BRICHOS (in panel (a), residues 140–197) and Bri2 BRICHOS (in panel (b), residues 160–220).

FIGURE 4

Structures of BRICHOS assemblies. (a) proSP‐C BRICHOS trimer (PDB 2yad) with the salt bridges highlighted (blue and red). (b) Cryo‐EM structural model of the Bri2 BRICHOS oligomer, with 24 subunits, where hydrophobic residues in the loop region (red) are highlighted.

FIGURE 5

Grammar of the BRICHOS molecular chaperone functions and treatment potential. (a) BRICHOS molecular chaperone functions and blood–brain barrier permeability depends on the assembly state which can be modulated by targeted mutagenesis. (b) BRICHOS can cross the blood–brain barrier and overexpression or intravenous administration in an AD model showed positive effects. See text for details. AD, Alzheimer's disease.