Towards understanding of allostery in MALT1: a possible role of interdomain motions as revealed by NMR and AlphaFold

Abstract

ABSTRACTMucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) has emerged as an attractive target for the development of modulatory compounds, particularly in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1(PCASP-Ig3)339–719has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained largely unexplored. We present here inaugural dynamic analyses of the apo MALT1(PCASP-Ig3)339–719form along with its mutated variant, E549A. This investigation harnessed an array of NMR relaxation techniques, including longitudinal and transverse15N auto-relaxation, heteronuclear NOE, transverse cross-correlated relaxation and NOE measurements between side-chain methyl groups. Our findings unequivocally confirm that MALT1(PCASP-Ig3)339–719exists solely as a monomer in solution, and demonstrate that the two domains display semi-independent movements in relation to each other. Our extensive dynamic study, covering a range of time scales, along with the assessment of diverse conformational populations for MALT1(PCASP-Ig3)339–719, by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, shed light at potential mechanisms underlying the allosteric regulation of this enzyme, and the specific importance of interdomain motions.