Review
Membrane mechanisms for signal transduction: The coupling of the meso-scale raft domains to membrane-skeleton-induced compartments and dynamic protein complexes

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Abstract

Virtually all biological membranes on earth share the basic structure of a two-dimensional liquid. Such universality and peculiarity are comparable to those of the double helical structure of DNA, strongly suggesting the possibility that the fundamental mechanisms for the various functions of the plasma membrane could essentially be understood by a set of simple organizing principles, developed during the course of evolution. As an initial effort toward the development of such understanding, in this review, we present the concept of the cooperative action of the hierarchical three-tiered meso-scale (2–300 nm) domains in the plasma membrane: (1) actin membrane-skeleton-induced compartments (40–300 nm), (2) raft domains (2–20 nm), and (3) dynamic protein complex domains (3–10 nm). Special attention is paid to the concept of meso-scale domains, where both thermal fluctuations and weak cooperativity play critical roles, and the coupling of the raft domains to the membrane-skeleton-induced compartments as well as dynamic protein complexes. The three-tiered meso-domain architecture of the plasma membrane provides an excellent perspective for understanding the membrane mechanisms of signal transduction.

Highlights

► The plasma membrane exhibits the three-tiered meso-scale domain architecture. ► The first tier is actin membrane-skeleton-induced compartments (partitioning). ► The second tier consists of raft domains with enormously varied sizes and lifetimes. ► The third tier is made of dynamic protein complex domains. ► Raft domains co-exist and work cooperatively with the domains of other tiers.

Section snippets

Introduction: general strategies for functional organization of the plasma membrane (membrane mechanisms)

In recent years, our understanding of the plasma membrane has advanced far beyond the textbook model of Singer and Nicolson [1]. Such new knowledge should be applied to research for the mechanistic understanding of plasma membrane functions. However, cell and developmental biologists and biomedical researchers are only slowly grasping the critically important, new concepts regarding the molecular mechanisms and the dynamic structures in the plasma membrane.

In this review, we will summarize our

Hypothesis of the hierarchical three-tiered meso-scale domain architecture of the plasma membrane

As an initial effort for developing such a general, fundamental understanding of the membrane mechanisms, we propose the concept of the hierarchical three-tiered meso-scale (2–300 nm) domain architecture of the plasma membrane (Fig. 1). In this review, we hope to persuade the readers that we can obtain an excellent perspective of the functional mechanisms of the plasma membrane by using this concept of the hierarchical three-tiered meso-domain architecture of the plasma membrane, in which all

Co-existence of actin-induced membrane compartments and raft domains in a single plasma membrane

Surprisingly, quite a few researchers appear to consider the actin-induced membrane compartments and the raft domains as warring either-or concepts. However, we found no evidence showing that one of them exclusively exists in the plasma membrane. On the contrary, all of the available data indicate the co-existence of the actin-membrane-skeleton-induced membrane compartments and the raft domains in a single plasma membrane. Therefore, another main aim of this review is to convince the readers

New molecular mechanisms revealed by fast single-molecule imaging

Recent developments in single-molecule techniques that are applicable to studies of living cells have provided researchers the unprecedented ability to directly observe the movement, assembly, and even activation of individual molecules in the plasma membrane [2], [30], [31], [32], [33]. High-speed single-molecule imaging and tracking methods have turned out to be particularly useful. Video-rate imaging, with a frame rate of 30 frames per second, is generally used in our normal daily lives,

The first tier: membrane-skeleton-induced compartments (partitioning)

The partitioning of the plasma membrane by the actin-based membrane skeleton and its associated TM proteins is summarized in the following eight points in this review. Due to space limitations, fuller accounts of the membrane-skeleton-induced compartments are published elsewhere [34].

The second tier: meso-scale raft domains

The concept of raft domains is still being developed. However, it is becoming clear that for the proper development of the raft fields, two key features of the raft domains should clearly be understood. (1) The raft domain properties are distinctly different between before and after stimulation. Therefore, raft domains before and after stimulation should never be mixed in the discussion except for the cases where stimulation-induced changes of raft domains are considered. (2) Since raft domains

The third tier: dynamic protein complex domains

We consider three types of “dynamic protein complex domains”, as shown in Fig. 8 (3):

  • (3a) oligomers of membrane-anchored proteins and protein complexes based on them,

  • (3b) coat-protein-facilitated domains,

  • (3c) scaffolding-protein-induced protein complexes.

Increasingly more researchers have started considering that signal transduction is performed not only by the collision or interaction of two molecules, but also by the multimolecular assemblies in/on the plasma membrane. Such multimolecular

Conclusions

The plasma membrane amplifies and modulates the signal received from the outside world, multiplexes it with other signals, branches it into many cytoplasmic signaling pathways with varied signal levels, and spreads it two-dimensionally along the plasma membrane as well as three-dimensionally by endocytosis. Thus, the plasma membrane works like a network of many computers that is connected to enormous numbers of sensors and actuators. However, the analogy stops here. In the electronic circuit of

Acknowledgements

We thank all of the members of the Kusumi Lab for fruitful discussions and critical reading of this manuscript, and Mr. Kohji Kanemasa for preparing the figures. This work was supported in part by Grants-in-Aid for Scientific Research from the MEXT (AK, KGNS, and TKF) and by Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (KGNS). R.C. is a recipient of the Postdoctoral Fellowship for Foreign Researchers, awarded by the Japan Society for the

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