Active regulation mechanisms of LLPS and MLOs biogenesis

Fernández-Alvarez, Ana Julia; Thomas, María Gabriela; Giudice, Jimena; Boccaccio, Graciela Lidia

doi:10.1016/b978-0-12-823967-4.00005-1

Cited by 1 publication

(1 citation statement)

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“…20 Indeed, the LCDs can drive the formation of extended biomolecular condensates and MLOs by promoting LLPS. 21,22 Together, these evidences strongly suggest that the Nterminal region of TFIP11, including the two IDRs and the G-Patch domain, play a central role in promoting not only the interactions with spliceosomal proteins but also with CBs scaffold protein, such as coilin, and are therefore of crucial importance to TFIP11 function.…”

Section: Introductionmentioning

confidence: 94%

Intrinsic Disorder and Salt-dependent Conformational Changes of the N-terminal Region of TFIP11 Splicing Factor

Juniku,

Mignon,

Carême

et al. 2024

Preprint

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Tuftelin Interacting Protein 11 (TFIP11) was recently identified as a critical human spliceosome assembly regulator. Indeed, it is involved in many biological functions including the interaction with multiple spliceosome key proteins and its localisation in several membrane-less organelles. However, there is a lack of structural information on TFIP11, which limits the rationalisation of its biological role. TFIP11 has been predicted as a highly disordered protein, and specifically concerning its N-terminal (N-TER) region. Intrinsically disordered proteins (IDPs) lack a defined tertiary structure, existing as a dynamic conformational ensemble, which favours their role as hubs in protein-protein and protein-RNA interaction networks. Furthermore, IDPs are involved in liquid-liquid phase separation (LLPS) which drives the formation of subnuclear compartments. In this study, we have refined the disorder prediction of TFIP11 N-TER region and subsequently performed all-atom molecular dynamics (MD) simulations to assess its conformational flexibility and the interplay between their different N-TER domains. We further confirm that TFIP11 may be described as a polyampholyte IDP with a flexible conformation. Furthermore, since LLPS formation and IDP conformational changes are salt-dependent phenomena we have investigated by MD simulations the influence of salt concentration in shaping the conformational ensemble of the N-TER region of TFIP11. Increasing the salt concentration enhances the flexibility of the TFIP11 N-TER conformation, which presents a fuzzier conformational landscape, a more globular shape, and an unstructured arrangement that could favor LLPS segregation and protein-RNA interaction.Abstract Figure

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Section: Introductionmentioning

confidence: 94%