TY - JOUR

T1 - Mass Spectrometry and Machine Learning Reveal Determinants of Client Recognition by Antiamyloid Chaperones

AU - Osterlund, Nicklas

AU - Vosselman, Thibault

AU - Leppert, Axel

AU - Graslund, Astrid

AU - Jornvall, Hans

AU - Ilag, Leopold L.

AU - Marklund, Erik G.

AU - Elofsson, Arne

AU - Johansson, Jan

AU - Sahin, Cagla

AU - Landreh, Michael

PY - 2022

Y1 - 2022

N2 - The assembly of proteins and peptides into amyloid fibrils is causally linked to serious disorders such as Alzheimer’s disease. Multiple proteins have been shown to prevent amyloid formation in vitro and in vivo, ranging from highly specific chaperone–client pairs to completely nonspecific binding of aggregation-prone peptides. The underlying interactions remain elusive. Here, we turn to the machine learning–based structure prediction algorithm AlphaFold2 to obtain models for the nonspecific interactions of β-lactoglobulin, transthyretin, or thioredoxin 80 with the model amyloid peptide amyloid β and the highly specific complex between the BRICHOS chaperone domain of C-terminal region of lung surfactant protein C and its polyvaline target. Using a combination of native mass spectrometry (MS) and ion mobility MS, we show that nonspecific chaperoning is driven predominantly by hydrophobic interactions of amyloid β with hydrophobic surfaces in β-lactoglobulin, transthyretin, and thioredoxin 80, and in part regulated by oligomer stability. For C-terminal region of lung surfactant protein C, native MS and hydrogen–deuterium exchange MS reveal that a disordered region recognizes the polyvaline target by forming a complementary β-strand. Hence, we show that AlphaFold2 and MS can yield atomistic models of hard-to-capture protein interactions that reveal different chaperoning mechanisms based on separate ligand properties and may provide possible clues for specific therapeutic intervention.

AB - The assembly of proteins and peptides into amyloid fibrils is causally linked to serious disorders such as Alzheimer’s disease. Multiple proteins have been shown to prevent amyloid formation in vitro and in vivo, ranging from highly specific chaperone–client pairs to completely nonspecific binding of aggregation-prone peptides. The underlying interactions remain elusive. Here, we turn to the machine learning–based structure prediction algorithm AlphaFold2 to obtain models for the nonspecific interactions of β-lactoglobulin, transthyretin, or thioredoxin 80 with the model amyloid peptide amyloid β and the highly specific complex between the BRICHOS chaperone domain of C-terminal region of lung surfactant protein C and its polyvaline target. Using a combination of native mass spectrometry (MS) and ion mobility MS, we show that nonspecific chaperoning is driven predominantly by hydrophobic interactions of amyloid β with hydrophobic surfaces in β-lactoglobulin, transthyretin, and thioredoxin 80, and in part regulated by oligomer stability. For C-terminal region of lung surfactant protein C, native MS and hydrogen–deuterium exchange MS reveal that a disordered region recognizes the polyvaline target by forming a complementary β-strand. Hence, we show that AlphaFold2 and MS can yield atomistic models of hard-to-capture protein interactions that reveal different chaperoning mechanisms based on separate ligand properties and may provide possible clues for specific therapeutic intervention.

KW - PROSURFACTANT PROTEIN-C

KW - BRICHOS DOMAIN

KW - ION MOBILITY

KW - AMYLOID FIBRILLATION

KW - BINDING-SITES

KW - GAS-PHASE

KW - BETA

KW - TRANSTHYRETIN

KW - AGGREGATION

KW - INSIGHTS

U2 - 10.1016/j.mcpro.2022.100413

DO - 10.1016/j.mcpro.2022.100413

M3 - Journal article

C2 - 36115577

VL - 21

JO - Molecular and Cellular Proteomics

JF - Molecular and Cellular Proteomics

SN - 1535-9476

IS - 10

M1 - 100413

ER -