OAF: a new member of the BRICHOS family

Abstract

Summary The ten known BRICHOS domain-containing proteins in humans have been linked to an unusually long list of pathologies, including cancer, obesity and two amyloid-like diseases. BRICHOS domains themselves have been described as intramolecular chaperones that act to prevent amyloid-like aggregation of their proteins' mature polypeptides. Using structural comparison of coevolution-based AlphaFold models and sequence conservation, we identified the Out at First (OAF) protein as a new member of the BRICHOS family in humans. OAF is an experimentally uncharacterised protein that has been proposed as a candidate biomarker for clinical management of COVID-19 infections. Our analysis revealed how structural comparison of AlphaFold models can discover remote homology relationships and lead to a better understanding of BRICHOS domain molecular mechanism. Supplementary information Supplementary data are available at Bioinformatics Advances online.

Structural homology screens reveal host-derived poxvirus protein families impacting inflammasome activity

“…Freed from constraints in host genomes, individual domains and combinations thereof may diverge to acquire new functions, with viral genomes serving as a testbed of evolutionary innovation. Our study joins a growing body of work demonstrating the transformative power of structural modeling in identifying evolutionary connections 10 , 54 , 55 and informing mechanistic study. 11 The ability to detect distant homology is especially important for hybrid proteins such as C1, where global homology searches may be inconclusive ( Figures 3A – 3C ).…”

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

“…To date, >3000 BRICHOS domain‐containing proteins, including species variants, have been identified and based on amino acid sequence alignments, they can be phylogenetically grouped into 14 families, that is, integral membrane protein 2A (ITM2A, also called Bri1), ITM2B (also called Bri2), ITM2C (also called Bri3), group I, group II, gastrokine‐1 (GKN1), gastrokine‐2 (GKN2), gastrokine‐3 (GKN3), tenomodulin (TNMD), chondromodulin (CNMD), proSP‐C, BRICHOS‐containing domain 5 (BRICD5), Out at First (OAF) protein, and antimicrobial peptide (AMP) (Chen et al, 2022 ; Sanchez‐Pulido & Ponting, 2022 ). Among these 14 BRICHOS families, 10 families are found in humans (Figure 1c ) and several members are associated with severe diseases like cancer, dementia, and COVID‐19 (Hedlund et al, 2009 ; Sanchez‐Pulido & Ponting, 2022 ). The physiological functions of the BRICHOS‐containing proproteins are largely unknown, the only exceptions being proSP‐C and Bri2.…”

“…The BRICHOS domains from different families share low pairwise sequence identities (down to <10% between families, Figure 2a ) but a strong consensus in their predicted secondary structures, suggesting that the BRICHOS structure is widely preserved (Knight et al, 2013 ; Sanchez‐Pulido et al, 2002 ). Therefore, advances in machine learning‐based protein structure prediction algorithms like AlphaFold2 and RosettaFold with homology modeling have already enabled the identification of a new BRICHOS domain‐containing protein (OAF) and may reveal further unknown BRICHOS proteins (Baek et al, 2021 ; Jumper et al, 2021 ; Sanchez‐Pulido & Ponting, 2022 ). The conserved tertiary structure of the BRICHOS domain is characterized by a central β‐sheet that is flanked by two α‐helices (1 and 2; Figure 1d ).…”

Structural homology screens reveal poxvirus-encoded proteins impacting inflammasome-mediated defenses

“…Freed from constraints in host genomes, individual domains and combinations thereof may diverge to acquire new functions, with viral genomes serving as a "testbed" of evolutionary innovation. Our study joins a growing body of work demonstrating the transformative power of structural modeling in identifying evolutionary connections 11,50,51 and informing mechanistic study 12 . The ability to detect distant homology is especially important for "hybrid" proteins such as C1, where global homology searches may be inconclusive (Figures 3A-C).…”