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Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses

Wallerstein, Johan LU ; Han, Xiao ; Levkovets, Maria ; Lesovoy, Dmitry ; Malmodin, Daniel ; Mirabello, Claudio ; Wallner, Björn ; Sun, Renhua ; Sandalova, Tatyana and Agback, Peter , et al. (2024) In Communications Biology 7.
Abstract
Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR 15N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time... (More)
Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR 15N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme. (Less)
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publishing date
type
Contribution to journal
publication status
published
in
Communications Biology
volume
7
article number
868
pages
18 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:39014105
  • scopus:85198723733
ISSN
2399-3642
DOI
10.1038/s42003-024-06558-y
language
English
LU publication?
no
id
276b665c-b80d-4b0b-8904-0e23f2928fd3
alternative location
https://rdcu.be/dQDY7
date added to LUP
2024-08-12 13:33:36
date last changed
2024-08-16 14:46:03
@article{276b665c-b80d-4b0b-8904-0e23f2928fd3,
  abstract     = {{Mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is an attractive target for the development of modulatory compounds in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1 has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained unexplored. We present here dynamic analyses of the apo MALT1 form along with the E549A mutation. This investigation used NMR <sup>15</sup>N relaxation and NOE measurements between side-chain methyl groups. Our findings confirm that MALT1 exists as a monomer in solution, and demonstrate that the domains display semi-independent movements in relation to each other. Our dynamic study, covering multiple time scales, along with the assessment of conformational populations by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, put the side chain of residue W580 in an inward position, shedding light at potential mechanisms underlying the allosteric regulation of this enzyme.}},
  author       = {{Wallerstein, Johan and Han, Xiao and Levkovets, Maria and Lesovoy, Dmitry and Malmodin, Daniel and Mirabello, Claudio and Wallner, Björn and Sun, Renhua and Sandalova, Tatyana and Agback, Peter and Karlsson, Göran and Achour, Adnane and Agback, Tatiana and Orekhov, Vladislav}},
  issn         = {{2399-3642}},
  language     = {{eng}},
  month        = {{07}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Communications Biology}},
  title        = {{Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses}},
  url          = {{http://dx.doi.org/10.1038/s42003-024-06558-y}},
  doi          = {{10.1038/s42003-024-06558-y}},
  volume       = {{7}},
  year         = {{2024}},
}