Intrinsic disorder in membraneless organelles: necessary, sufficient, or neither?

The discovery that proteins and nucleic acids can self-organize into membraneless compartments via liquid–liquid phase separation (LLPS) has transformed our understanding of cellular organization. Intrinsically disordered regions (IDRs) are often enriched in membraneless organelles (MLOs) and have been proposed as central drivers of this process. However, whether intrinsic disorder is necessary, sufficient, or merely one of several contributing features is worth discussing. This article examines recent evidence highlighting the duality of IDRs: while their conformational flexibility and multivalent interactions promote condensate formation, ordered domains, RNA scaffolds, and post-translational modifications also play decisive roles. Emerging research reveals that phase separation can also occur in the absence of extensive disorder, which suggests that disorder is not necessary for condensate formation. Conversely, many intrinsically disordered proteins fail to undergo LLPS without cooperative partners or specific sequence features, suggesting that disorder alone is not sufficient. We discuss critical gaps, such as the quantitative determinants of LLPS and the physiological relevance of MLOs, and outline future avenues for disentangling these complex relationships.