Guide Multistate GTPase Control Co-translational Protein Targeting (Springer Theses)

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Protein Targeting

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If your order has not yet been shipped you will need to send Dymocks Online an email advising the error and requesting a change in details. If your order has a status of "packed" or "shipped" we will not be able to guarantee any change in shipping details. Here, we show that this series of rearrangements during SRP—SR binding and activation provide important control points to drive and regulate protein targeting.

Using real time fluorescence, we showed that the cargo for SRP—ribosomes translating nascent polypeptides with signal sequences—accelerates SRP—SR complex assembly over fold, thereby driving rapid delivery of cargo to the membrane. A series of subsequent rearrangements in the SRP—SR GTPase complex provide important driving forces to unload the cargo during late stages of protein targeting.

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Further, the cargo delays GTPase activation in the SRP—SR complex by 8- to fold, creating an important time window that could further improve the efficiency and fidelity of protein targeting. Thus the SRP and SR GTPases, without recruiting external regulatory factors, constitute a self-sufficient system that provides exquisite spatial and temporal control of a complex cellular process. Proper localization of proteins to their correct cellular destinations is essential for all cells.

However, the precise mechanism by which high fidelity is achieved in protein localization is not well understood for any targeting pathways.

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To probe this fundamental question we investigated targeting of proteins by the signal recognition particle SRP. It was generally thought that fidelity arises from the inability of SRP to bind strongly to incorrect cargos. Here we show that incorrect cargos are further rejected through a series of fidelity checkpoints during subsequent steps of targeting, including complex formation between the SRP and SRP receptor SR and kinetic proofreading through GTP hydrolysis.

Thus the SRP pathway achieves a high fidelity through the cumulative effect of multiple checkpoints; this principle may be generally applicable to other complex cellular pathways that need to recognize degenerate signals or discriminate between correct and incorrect substrates based on minor differences.

Print ISBN Electronic ISBN Our understanding of the structure and conformational energetics of MPs lags behind that of water-soluble proteins. The first experimentally determined structure of a MP was generated in the photosynthetic reaction center , which was nearly 30 years after completion of the first high resolution structure of a water-soluble protein myoglobin, With reverence, we refer the reader to some of the excellent previous reviews of MP folding involving isolated proteins, most of which include coverage of topics that we do not endeavor to rereview in this work, in particular the structural basis for MP stability.

An emerging frontier in studies of MP folding is integration of studies of MP folding using purified proteins with studies of the folding of MPs in the context of living cells. There has been a wealth of parallel progress in recent years in these disciplines, which now have much to offer each other. Additional impetus for bridge-building is provided by recent advances in human genomics, which have highlighted numerous relationships between defects in MP folding and human disease that may be addressable using emerging chemical tools.

Here, we endeavor to review results from studies of purified MPs that are of particular importance for understanding how MPs fold in the context of living cells. We also examine recent progress in the myriad of studies devoted to identifying the key molecular players for managing MP folding and misfolding in vivo. In particular, we focus on the chaperones and other proteins that comprise the folding quality control system of the endoplasmic reticulum ER , which serves as the primary site of MP assembly in eukaryotic cells. Finally, we examine how MP misfolding under physiological conditions contributes to numerous diseases and examine emerging chemical biology and medicinal chemistry approaches that directly address defects in MP folding to treat these diseases.

Natively folded MPs adopt conformational states that are partly, or in some cases nearly completely, embedded within the membrane. For both classes of MPs, polar side chains near the edge of TM domains interact with lipid head groups and water molecules in a manner that helps stabilize their native topological orientation in the membrane. This energetic constraint restricts the number of topological orientations that are kinetically accessible to integral MPs. The Sec translocon effectively circumvents the insertion barrier by providing hydrophobic segments access to the membrane core through a lateral opening within its transbilayer pore.

Single Molecule Fluorescence Spectroscopy of the Folding of a Repeat Protein Springer Theses Pdf

After MP translation, the physicochemical properties of the lipid bilayer enforce constraints on the conformational equilibria of integral MPs. For instance, the hydrophobic nature of the membrane core imposes a steep energetic penalty associated with the solvation of unpaired hydrogen bond donors and acceptors. As a result of these energetic constraints, the central portions of naturally evolved transmembrane segments are enriched in the hydrophobic amino acids, and polar residues are typically rare within the membrane core Figure 1. This sequence bias is particularly pronounced on the lipid-exposed surface of the TM domain.


This abundance of polar groups provides ample opportunities to form intramolecular hydrogen bonds in a manner that provides some structural plasticity. The residues in these extended membrane-buried segments appear to have unsatisfied backbone hydrogen bonding potentials and possibly interact with water molecules.

High Resolution Image. MPs are often sensitive to the physical properties of their bilayer solvent.

Most lipids are roughly cylindrical in shape and are arranged with their long axes orthogonal to the plane of the membrane, which allows them to neatly pack into a two-dimensional sheets. However, in part due to the abundance of unsaturated fatty acids in mesophilic organisms, there is typically a gradient of lateral pressure extending from the bilayer interface into the highly dynamic bilayer core, where the fluidity can approach that of liquid hydrocarbons. This manipulation of curvature is required for many cellular processes such as vesicle budding, transport, and fusion.

In some cases, TM helices are tilted relative to the bilayer normal, which may occur as a result of a mismatch between the length of the TM domain and the thickness of the membrane hydrophobic mismatch, Figure 2. Under nonphysiological conditions in which the concentration of MPs within the bilayer is typically much lower, membrane thickness is largely determined by lipid composition. Saturated acyl chains produce thicker bilayers, whereas unsaturated chains dynamically splay outward in a manner that allows the two leaflets to pack more closely together.

In contrast, the rigid, flat surface of cholesterol stabilizes extended conformational states of adjacent phospholipid acyl chains in a manner that typically increases membrane thickness and lipid conformational order. Indeed, Bowie and co-workers have argued that the total number of possible folds that are accessible to MPs is limited relative to soluble proteins. A distinctive trait of plasma, endosome, and lysosome membranes relative to those of the nucleus, mitochondria, endoplasmic reticulum, and Golgi is the presence of higher concentrations of both cholesterol and sphingolipids in the former Figure 3.

In this regard, an interesting preliminary observations is that high levels of cholesterol in the membrane tend to promote alignment of otherwise tilted transmembrane helices with the bilayer normal. The original fluid mosaic model 98 continues to serve as a point of reference for our understanding of the organization and dynamics of biological membranes. Nevertheless, the simplistic assumptions of this model have been subject to a variety of clarifications, revisions, and updates over the years. It has long been appreciated that bilayers are capable of forming a liquid-ordered phase L o at certain temperatures and lipid compositions especially those rich in cholesterol and sphingolipids.

Macroscopic L d and L o phases are capable of coexisting within a single lipid vesicle in a manner that can be visualized by confocal fluorescence microscopy. For this reason, the very existence of lipid rafts and their potential biological relevance have proven controversial. The existence of lipid rafts is typically debated in the context of eukaryotic plasma membranes. Direct observation of coexisting phases in the plasma membranes of living cells has proven extremely challenging.

Over the past 15 years, a classic series of studies from the Veatch, Keller, and Baird laboratories have offered a satisfying explanation for the dynamic coexistence of less-ordered and more-ordered phases within plasma membranes. At a critical point, the compositions and populations of both phases are equal and lipids randomly fluctuate between phases in a manner mediated by thermal energy k B T.

Below T c at fixed membrane composition the membrane demixes into two stable macroscopic phases. Above T c , the phases appear to mix into a single phase. The shapes of these transient ordered domains are irregular as a result of the reduced line tension between phases. Notably, the physical basis for this framework can be modeled reasonably well using a two-dimensional Ising model, which provides a mechanistic framework that can be used to rationalize membrane organization.

These phases likely have only slight differences in composition and order relative to the comingled disordered phase. Plasma membranes do contain more-highly disordered domains in coexistence with more fluid microdomains. However, not only are these domains transient—mere fluctuations!

The biological implications of critical behavior within biological membranes is just beginning to be explored. For example, critical behavior provides a quantitative framework that accounts for how certain receptors undergo spatial clustering and oligomerization. This is clearly an avenue for future exploration.

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At the same time, we note that appreciation of critical behavior in biological membrane will ultimately need to be melded with what is understood about of how cytoskeletal attachment points, lipid asymmetry, and MP crowding alter membrane-based phenomena, including MP folding and stability. Longstanding interest in how lipids interact with MPs has heightened in recent years as advances in both computational and experimental structural biology especially mass spectrometry have provided new details on the nature of these interactions. Stoichiometric complexes between certain proteins and lipids have been found to promote the stability and organization of native MP complexes.

In addition to adapting to the chemical and physical properties of the membrane environment, native MP conformations must, to some extent, also have evolved to tolerate variations in membrane lipid composition. Each of these organelles has its own distinctive lipid composition Figure 3 , 91,92 which likely plays a role in the tuning of the structure and function of resident MPs.