https://doi.org/10.1101/2025.05.09.653163
요약
- 이 논문은 코일-코일 단백질(coiled-coil proteins)이 비특이적 상호작용(nonspecific interactions)만으로도 액-액 상분리(LLPS)를 유도할 수 있음을 보여줍니다: 기존에는 특정 결합 특성 또는 sticker–spacer 패턴이 필요하다고 여겨졌으나, 이 논문은 단순한 물리적 상호작용만으로도 상분리가 가능함을 강조합니다.
- 코스그레인드 모델(coarse-grained model)을 사용해 다양한 유형의 coiled-coil 단백질 서열을 시뮬레이션하며, 단백질 간 비특이적 인력이 상분리 역학에 어떤 영향을 미치는지 정량적으로 분석합니다.
- 단순한 정전기적, 소수성 상호작용만으로도 고농도 상태에서 응축체가 형성되며, 이는 생체 내 복잡계에서도 유사한 상분리 메커니즘이 작동할 수 있음을 시사합니다.
- coiled-coil 단백질은 다양한 생물학적 환경에서 자주 관찰되며, 이들의 상분리 능력은 기능적 조절 또는 병리학적 응집과도 연관될 수 있습니다.
- 결론적으로, 특정 결합 모티프가 없어도 단순한 물리적 상호작용만으로도 상분리 현상이 발생할 수 있으며, 이는 단백질 기반 신소재 디자인이나 질병 모델링에 응용될 수 있습니다.
Abstract
Liquid-liquid phase separation (LLPS) is one mechanism that cells can use to organize biomolecules spatially and functionally. Some coiled-coil (CC) proteins, such as the centrosomal proteins pericentrin and spd-5, are thought to LLPS, but it is currently unknown what parts of these proteins facilitate the process. It is thought, however, that the numerous CC domains in these proteins might be contributing to their LLPS. We recently showed, using computational studies and designed proteins, that CC domains can facilitate LLPS through specific interactions between the CC domains themselves, meaning that each CC was designed to interact only with a subset of other CCs in the system. This is in contrast to nonspecific interactions, where all CCs would be able to interact with all other CCs in the system, which is akin to some interactions (e.g. π–π) seen in phase-separating intrinsically disordered proteins. Because the specificity of interactions between natural CC domains is tunable in a sequence-dependent fashion, CC domains present a unique system that allows us to investigate the contributions of specific versus nonspecific interactions on LLPS. We show, in our computational system, that CC proteins with nonspecific interactions can LLPS but with less propensity compared to specific interactions. The LLPS propensity of CC proteins with nonspecific interactions can be improved by altering the structure and dynamics of linker segments, without directly changing the specificity of interactions. We also demonstrate that the number of intra-chain CC contacts plays a direct role in determining LLPS for nonspecifically interacting proteins. These results have broad implications for the role of linker segments—protein features beyond the interaction domains e.g. ‘stickers’—in protein LLPS and the formation of biomolecular condensates.