Form Meets Function: Oligomerisation Propensity and the Anti-Amyloid Activity of DNAJB6b
(2025) KFKM05 20261Biophysical Chemistry
- Abstract
- The chaperone protein DNAJB6b exhibits intrinsic activity in inhibiting amyloid fibril formation, although the underlying mechanism remains unclear. A key region, comprising residues 132-183 and rich in serine and threonine residues, commonly referred to as the “S/T region”, has been shown to play a critical role in this function. While deletion of the S/T region does not disrupt the folding of DNAJB6b’s N- and C-terminal domains, it markedly reduces the anti-amyloid activity of the chaperone and disrupts its ability to form polydisperse oligomers, resulting instead in a monomeric protein in solution. In this study, we investigated the role of the S/T region by characterizing mutants with partial deletions within this segment. By comparing... (More)
- The chaperone protein DNAJB6b exhibits intrinsic activity in inhibiting amyloid fibril formation, although the underlying mechanism remains unclear. A key region, comprising residues 132-183 and rich in serine and threonine residues, commonly referred to as the “S/T region”, has been shown to play a critical role in this function. While deletion of the S/T region does not disrupt the folding of DNAJB6b’s N- and C-terminal domains, it markedly reduces the anti-amyloid activity of the chaperone and disrupts its ability to form polydisperse oligomers, resulting instead in a monomeric protein in solution. In this study, we investigated the role of the S/T region by characterizing mutants with partial deletions within this segment. By comparing the first and second halves of the region, we show that oligomerisation is driven by the specific residues or segments rather than linker length. We also observed phase separation in two of the deletion mutants. Our findings also suggest that the features governing oligomerisation and chaperone activity are indirectly linked, and that all three investigated mutants exhibited poorer functionality compared to the full-length protein. (Less)
- Popular Abstract
- The cellular protein landscape resembles a dense forest, full of intricate and dynamic interactions. Sometimes, a single misfolded protein acts like a spark, igniting a wildfire of aggregation that spreads and damages its healthy surroundings. Such uncontrolled protein aggregation is a hallmark of neurodegenerative diseases like Alzheimer’s and Parkinson’s.
To combat this threat, cells rely on molecular firefighters called chaperones. One particularly effective chaperone is DNAJB6b, which prevents misfolded proteins from assembling into toxic amyloid fibrils. A key part of DNAJB6b’s structure is called the S/T stretch. This region is crucial both for its function and for its ability to form oligomers, which are small clusters of the... (More) - The cellular protein landscape resembles a dense forest, full of intricate and dynamic interactions. Sometimes, a single misfolded protein acts like a spark, igniting a wildfire of aggregation that spreads and damages its healthy surroundings. Such uncontrolled protein aggregation is a hallmark of neurodegenerative diseases like Alzheimer’s and Parkinson’s.
To combat this threat, cells rely on molecular firefighters called chaperones. One particularly effective chaperone is DNAJB6b, which prevents misfolded proteins from assembling into toxic amyloid fibrils. A key part of DNAJB6b’s structure is called the S/T stretch. This region is crucial both for its function and for its ability to form oligomers, which are small clusters of the protein. Our goal was to determine whether oligomer formation is necessary for chaperone function or if these two properties are independent.
This thesis project studied DNAJB6b variants with partial deletions in the S/T stretch to explore the relationship between structure, oligomerisation, and function. Interestingly, some mutants formed oligomers efficiently but showed little ability to suppress aggregation. Conversely, others failed to oligomerise well but still retained some anti-aggregation activity. We also observed that the organisation of oligomers varied vastly between mutants, adding a layer of complexity.
These results suggest that while oligomerisation enhances DNAJB6b’s function, it is not sufficient on its own. The mechanisms controlling oligomer formation and chaperone activity are related but distinct. Understanding how these molecular firefighters work at a structural level is essential for developing new strategies to control protein aggregation in neurodegenerative diseases. By uncovering these details, we can better prevent and manage these damaging protein wildfires. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9208288
- author
- Björn, Lovisa LU
- supervisor
-
- Sara Linse LU
- Andreas Carlsson LU
- organization
- course
- KFKM05 20261
- year
- 2025
- type
- H3 - Professional qualifications (4 Years - )
- subject
- keywords
- DNAJB6b, chaperone proteins, amyloid fibrils, protein aggregation, neurodegenerative diseases, S/T region, J-domain, oligomerisation, protein phase separation, protein structure-function relationship, molecular chaperones, protein misfolding, protein-protein interactions, Alzheimer’s disease, Parkinson’s disease, biophysical chemistry
- language
- English
- id
- 9208288
- date added to LUP
- 2025-07-07 10:08:33
- date last changed
- 2025-07-07 10:08:33
@misc{9208288,
abstract = {{The chaperone protein DNAJB6b exhibits intrinsic activity in inhibiting amyloid fibril formation, although the underlying mechanism remains unclear. A key region, comprising residues 132-183 and rich in serine and threonine residues, commonly referred to as the “S/T region”, has been shown to play a critical role in this function. While deletion of the S/T region does not disrupt the folding of DNAJB6b’s N- and C-terminal domains, it markedly reduces the anti-amyloid activity of the chaperone and disrupts its ability to form polydisperse oligomers, resulting instead in a monomeric protein in solution. In this study, we investigated the role of the S/T region by characterizing mutants with partial deletions within this segment. By comparing the first and second halves of the region, we show that oligomerisation is driven by the specific residues or segments rather than linker length. We also observed phase separation in two of the deletion mutants. Our findings also suggest that the features governing oligomerisation and chaperone activity are indirectly linked, and that all three investigated mutants exhibited poorer functionality compared to the full-length protein.}},
author = {{Björn, Lovisa}},
language = {{eng}},
note = {{Student Paper}},
title = {{Form Meets Function: Oligomerisation Propensity and the Anti-Amyloid Activity of DNAJB6b}},
year = {{2025}},
}