Dynamic shape changes of the plasma membrane are fundamental to many processes ranging from morphogenesis and cell migration to phagocytosis and viral propagation. Here we demonstrate that Exo70, a component of the exocyst complex, induces tubular membrane invaginations towards the lumen of synthetic vesicles in vitro and generates protrusions on the surface of cells. Biochemical analyses using Exo70 mutants and independent molecular dynamics simulations based on Exo70 structure demonstrate that Exo70 generates negative membrane curvature through an oligomerization-based mechanism. In cells, the membrane-deformation function of Exo70 is required for protrusion formation and directional cell migration. Exo70 thus represents a membrane-bending protein that may couple actin dynamics and plasma membrane remodeling for morphogenesis.
The physiological properties of biological soft matter are the product of collective interactions, which span many time and length scales. Recent computational modeling efforts have helped illuminate experiments that characterize the ways in which proteins modulate membrane physics. Linking these models across time and length scales in a multiscale model explains how atomistic information propagates to larger scales. This paper reviews continuum modeling and coarse-grained molecular dynamics methods, which connect atomistic simulations and single-molecule experiments with the observed microscopic or mesoscale properties of soft-matter systems essential to our understanding of cells, particularly those involved in sculpting and remodeling cell membranes.
In intracellular trafficking, a definitive understanding of the interplay between protein binding and membrane morphology remains incomplete. The authors describe a computational approach by integrating coarse-grained molecular dynamics (CGMD) simulations with continuum Monte Carlo (CM) simulations of the membrane to study protein–membrane interactions and the ensuing membrane curvature. They relate the curvature field strength discerned from the molecular level to its effect at the cellular length-scale. They perform thermodynamic integration on the CM model to describe the free energy landscape of vesiculation in clathrin-mediated endocytosis. The method presented here delineates membrane morphologies and maps out the free energy changes associated with membrane remodeling due to varying coat sizes, coat curvature strengths, membrane bending rigidities, and tensions; furthermore several constraints on mechanisms underlying clathrin-mediated endocytosis have also been identified, Their CGMD simulations have revealed the importance of PIP2 for stable binding of proteins essential for curvature induction in the bilayer and have provided a molecular basis for the positive curvature induction by the epsin N-terminal homology (EIMTH) domain. Calculation of the free energy landscape for vesicle budding has identified the critical size and curvature strength of a clathrin coat required for nucleation and stabilisation of a mature vesicle.
At the micron scale, where cell organelles display an amazing complexity in their shape and organization, the physical properties of a biological membrane can be better-understood using continuum models subject to thermal (stochastic) undulations. Yet, the chief orchestrators of these complex and intriguing shapes are a specialized class of membrane associating often peripheral proteins called curvature remodeling proteins (CRPs) that operate at the molecular level through specific protein-lipid interactions. We review multiscale methodologies to model these systems at the molecular as well as at the mesoscopic and cellular scales, and also present a free energy perspective of membrane remodeling through the organization and assembly of CRPs. We discuss the morphological space of nearly planar to highly curved membranes, methods to include thermal fluctuations, and review studies that model such proteins as curvature fields to describe the emergent curved morphologies. We also discuss several mesoscale models applied to a variety of cellular processes, where the phenomenological parameters (such as curvature field strength) are often mapped to models of real systems based on molecular simulations. Much insight can be gained from the calculation of free energies of membranes states with protein fields, which enable accurate mapping of the state and parameter values at which the membrane undergoes morphological transformations such as vesiculation or tubulation. By tuning the strength, anisotropy, and spatial organization of the curvature-field, one can generate a rich array of membrane morphologies that are highly relevant to shapes of several cellular organelles. We review applications of these models to budding of vesicles commonly seen in cellular signaling and trafficking processes such as clathrin mediated endocytosis, sorting by the ESCRT protein complexes, and cellular exocytosis regulated by the exocyst complex. We discuss future prospects where such models can be combined with other models for cytoskeletal assembly, and discuss their role in understanding the effects of cell membrane tension and the mechanics of the extracellular microenvironment on cellular processes.
Edited by Alex TokerSpatial and temporal control of actin polymerization is fundamental for many cellular processes, including cell migration, division, vesicle trafficking, and response to agonists. Many actin-regulatory proteins interact with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) and are either activated or inactivated by local PI(4,5)P 2 concentrations that form transiently at the cytoplasmic face of cell membranes. The molecular mechanisms of these interactions and how the dozens of PI(4,5)P 2sensitive actin-binding proteins are selectively recruited to membrane PI(4,5)P 2 pools remains undefined. Using a combination of biochemical, imaging, and cell biologic studies, combined with molecular dynamics and analytical theory, we test the hypothesis that the lateral distribution of PI(4,5)P 2 within lipid membranes and native plasma membranes alters the capacity of PI(4,5)P 2 to nucleate actin assembly in brain and neutrophil extracts and show that activities of formins and the Arp2/3 complex respond to PI(4,5)P 2 lateral distribution. Simulations and analytical theory show that cholesterol promotes the cooperative interaction of formins with multiple PI(4,5)P 2 headgroups in the membrane to initiate actin nucleation. Masking PI(4,5)P 2 with neomycin or disrupting PI(4,5)P 2 domains in the plasma membrane by removing cholesterol decreases the ability of these membranes to nucleate actin assembly in cytoplasmic extracts.
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