RIM and RIM-BP Form Presynaptic Active-Zone-like Condensates via Phase Separation

Wu, Xiandeng; Cai, Qixu; Shen, Zeyu; Chen, Xudong; Zeng, Menglong; Du, Shengwang; Zhang, Mingjie

doi:10.1016/j.molcel.2018.12.007

Cited by 178 publications

(218 citation statements)

References 47 publications

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“…Though many IDPs/IDRs involved in LLPS apply multisite electrostatic and aromatic interactions, dynamic coupled folding‐binding interactions mediated by specific recognition elements can also drive LLPS. For example, interactions between SH3 domain and proline‐rich motif are involved in the LLPS of the nephrin–NCK–N‐WASP system and the RIM–RIM‐BP system . PDZ domain‐mediated binding is required for phase separation of PSD scaffold proteins .…”

Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

“…For example, interactions between SH3 domain and proline-rich motif are involved in the LLPS of the nephrin-NCK-N-WASP system and the RIM-RIM-BP system. 189,190 PDZ domain-mediated binding is required for phase separation of PSD scaffold proteins. 191,192 Multivalent arginine-rich linear motifs interact with the NPM1 pentamer, leading to LLPS.…”

Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

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Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

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Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

Section: Dynamic Contacts and Fuzzy Interactionsmentioning

confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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“…Here, we have provided evidence that the GIT1/β-Pix condensates can be recruited to FAs via the GIT1/Paxillin interaction. Numerous observations point to the possibility that FAs, analogous to pre-and post-synaptic signaling assemblies in neurons 9,12 and signaling complexes in immune-synapses 53 , may also be assembled via phase separation. Both cryo-electron tomography and recent super-resolution light microscopy studies have revealed that FAs form specific electron-dense structures.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggests that formation of membrane-less compartments, also known as biomolecular condensates, via liquid-liquid phase separation is a new mechanism used by cells to concentrate biomolecules, including enzymes, at specific subcellular regions [1][2][3][4] . Membrane-less condensates seem to be widespread in cells and include cellular machineries such as P granule 5 , nucleoli 6 , centrosomes 7,8 , pre-and postsynaptic signaling apparatuses [9][10][11][12] , and stress granules 13,14 . Membrane-less biomolecular condensates display many unique features when compared to traditional stoichiometric assemblies of molecular complexes as well as membrane-enclosed cellular compartments [2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

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Phase separation-mediated formation of condensed GIT/PIX enzyme complex module for compartmentalized signaling

Zhu

Zhou

Xia

et al. 2019

Preprint

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Cells compartmentalize enzymes for broad physiological functions such as efficient metabolic reactions and spatiotemporally controlled signaling. A given enzyme or enzyme complex can participate in multiple cellular processes in response to different signal inputs by forming different cellular compartments. Here, we demonstrate that association of GIT1 and β-Pix, a pair of GTPase regulatory enzymes involved in diverse cellular processes, leads to autonomous condensation of the complex via phase separation without additional scaffolding molecules. The atomic structure of the GIT/PIX complex reveals the molecular basis governing the phase separation-mediated condensation of the GIT1/β-Pix complex. Importantly, the GIT1/β-Pix condensates can function as a versatile modular membrane-less organellelike structure for distinct cellular compartmentalization by binding to upstream proteins such as Paxillin in focal adhesions, Shank3 in neuronal synapses, and Scribble in cellular junctions. Thus, phase separation-mediated formation of condensed enzyme complexes provides a powerful way of dynamically concentrating limited amounts of cooperating enzymes to specific cellular compartments for optimal signaling.

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α‐Synuclein phase separation and amyloid aggregation are modulated by C‐terminal truncations

Huang

Wang

et al. 2022

FEBS Letters

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The aggregation of α‐synuclein (α‐Syn) is a key pathological hallmark of Parkinson's disease (PD). α‐Syn undergoes liquid‐liquid phase separation (LLPS) to drive amyloid aggregation. How the LLPS of α‐Syn is regulated remains largely unknown. Here, we discovered that the C‐terminal region modulates α‐Syn phase separation through electrostatic interactions. The wild‐type (WT) and PD disease‐related truncated α‐Syn can co‐exist in the condensates. The truncated α‐Syn could dramatically promote WT α‐Syn phase separation. Further studies demonstrated that the truncated α‐Syn accelerated WT α‐Syn turning to amyloid aggregates by modulation of phase separation. Together, our findings disclose the role of the C‐terminal domain in the LLPS of α‐Syn and pave the path for understanding the mechanism of truncated α‐Syn in PD pathology.

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RIM and RIM-BP Form Presynaptic Active-Zone-like Condensates via Phase Separation

Cited by 178 publications

References 47 publications

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Phase separation-mediated formation of condensed GIT/PIX enzyme complex module for compartmentalized signaling

α‐Synuclein phase separation and amyloid aggregation are modulated by C‐terminal truncations

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