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. 2023 Jan:346:107318.
doi: 10.1016/j.jmr.2022.107318.

A call to order: Examining structured domains in biomolecular condensates

Ryan W Tibble  1 , John D Gross  2
Affiliations

A call to order: Examining structured domains in biomolecular condensates

Ryan W Tibble et al. J Magn Reson. 2023 Jan.

Abstract

Diverse cellular processes have been observed or predicted to occur in biomolecular condensates, which are comprised of proteins and nucleic acids that undergo liquid-liquid phase separation (LLPS). Protein-driven LLPS often involves weak, multivalent interactions between intrinsically disordered regions (IDRs). Due to their inherent lack of defined tertiary structures, NMR has been a powerful resource for studying the behavior and interactions of IDRs in condensates. While IDRs in proteins are necessary for phase separation, core proteins enriched in condensates often contain structured domains that are essential for their function and contribute to phase separation. How phase separation can affect the structure and conformational dynamics of structured domains is critical for understanding how biochemical reactions can be effectively regulated in cellular condensates. In this perspective, we discuss the consequences phase separation can have on structured domains and outline NMR observables we believe are useful for assessing protein structure and dynamics in condensates.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1:
Figure 1:
Interactions control condensate formation and liquid-like properties. A, Condensate formation results from phase separation (top) and percolation (bottom). B, Intrinsically disordered regions often flank structured regions and promote liquid-liquid phase separation through weak, multivalent interactions. Disordered regions can also promote stable fibril formation through strong interactions following maturation of condensates.
Figure 2:
Figure 2:
Amino and nucleic acid derivatives used in biomolecular NMR. These labels have advantageous NMR relaxation properties useful for studying large macromolecular assemblies such as condensates. Observable signals are highlighted in pink.
Figure 3:
Figure 3:
Protein conjugation strategies for segmental labeling of proteins. A, Split intein can be fused to two polypeptide fragments (Seg1 and Seg2) that are subsequently ligated to form a single chain. B, SortaseA enzyme ligates a protein fragment (Seg2) with N-terminal glycine residues to its C-terminal recognition sequence in a second fragment (Seg1). C, SortaseA ligation applied to S. pombe decapping complex Dcp1/2 D, 1H-13C HSQC ILVMA spectrum of structured domains in segmentally-labeled Dcp1/2.
Figure 4:
Figure 4:
Potential effects of phase separation on structured domains. A, In dispersed solution, an IDR samples many conformational states, but one minor interaction may become stabilized in condensates and cause an emergent functional outcome for activity (i.e. repression, activation, etc.) B, The condensate environment can alter the conformational landscape of proteins in multiple ways, including changes to the rate of conformational exchange or the free energy of a given state.
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