Diversity of Structural, Dynamic, and Environmental Effects Explain a Distinctive Functional Role of Transmembrane Domains in the Insulin Receptor Subfamily.

Human InsR, IGF1R, and IRR receptor tyrosine kinases (RTK) of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes and are directly associated with many pathologies, including neurodegenerative diseases. The disulfide-linked dimeric structure of these receptors is unique among RTKs. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions.

Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer's Disease Development.

Alzheimer's disease is the most common type of neurodegenerative disease in the world. Genetic evidence strongly suggests that aberrant generation, aggregation, and/or clearance of neurotoxic amyloid-β peptides () triggers the disease. accumulates at the points of contact of neurons in ordered cords and fibrils, forming the so-called senile plaques.

Familial L723P Mutation Can Shift the Distribution between the Alternative APP Transmembrane Domain Cleavage Cascades by Local Unfolding of the Ε-Cleavage Site Suggesting a Straightforward Mechanism of Alzheimer's Disease Pathogenesis.

Alzheimer's disease is an age-related pathology associated with accumulation of amyloid-β peptides, products of enzymatic cleavage of amyloid-β precursor protein (APP) by secretases. Several familial mutations causing early onset of the disease have been identified in the APP transmembrane (TM) domain. The mutations influence production of amyloid-β, but the molecular mechanisms of this effect are unclear.

Membrane Elastic Deformations Modulate Gramicidin A Transbilayer Dimerization and Lateral Clustering.

Gramicidin A (gA) is a short β-helical peptide known to form conducting channels in lipid membranes because of transbilayer dimerization. The gA conducting dimer, being shorter than the lipid bilayer thickness, deforms the membrane in its vicinity, and the bilayer elastic energy contributes to the gA dimer formation energy. Likewise, membrane incorporation of a gA monomer, which is shorter than the lipid monolayer thickness, creates a void, thereby forcing surrounding lipid molecules to tilt to fill it.

Lateral Membrane Heterogeneity Regulates Viral-Induced Membrane Fusion during HIV Entry.

Sphingomyelin- and cholesterol- enriched membrane domains, commonly referred to as "rafts" play a crucial role in a large number of intra- and intercellular processes. Recent experiments suggest that not only the volumetric inhomogeneity of lipid distribution in rafts, but also the arrangement of the 1D boundary between the raft and the surrounding membrane is important for the membrane-associated processes. The reason is that the boundary preferentially recruits different peptides, such as HIV (human immunodeficiency virus) fusion peptide.

Phosphatidylcholine Membrane Fusion Is pH-Dependent.

Membrane fusion mediates multiple vital processes in cell life. Specialized proteins mediate the fusion process, and a substantial part of their energy is used for topological rearrangement of the membrane lipid matrix. Therefore, the elastic parameters of lipid bilayers are of crucial importance for fusion processes and for determination of the energy barriers that have to be crossed for the process to take place.

Structural basis of the signal transduction via transmembrane domain of the human growth hormone receptor.

Background: Prior studies of the human growth hormone receptor (GHR) revealed a distinct role of spatial rearrangements of its dimeric transmembrane domain in signal transduction across membrane. Detailed structural information obtained in the present study allowed elucidating the bases of such rearrangement and provided novel insights into receptor functioning.

Methods: We investigated the dimerization of recombinant TMD fragment GHR by means of high-resolution NMR in DPC micelles and molecular dynamics in explicit POPC membrane.

Switching between Successful and Dead-End Intermediates in Membrane Fusion.

Fusion of cellular membranes during normal biological processes, including proliferation, or synaptic transmission, is mediated and controlled by sophisticated protein machinery ensuring the preservation of the vital barrier function of the membrane throughout the process. Fusion of virus particles with host cell membranes is more sparingly arranged and often mediated by a single fusion protein, and the virus can afford to be less discriminative towards the possible different outcomes of fusion attempts. Formation of leaky intermediates was recently observed in some fusion processes, and an alternative trajectory of the process involving formation of π-shaped structures was suggested.

Pore formation in lipid membrane II: Energy landscape under external stress.

Lipid membranes are extremely stable envelopes allowing cells to survive in various environments and to maintain desired internal composition. Membrane permeation through formation of transversal pores requires substantial external stress. Practically, pores are usually formed by application of lateral tension or transmembrane voltage.

Pore formation in lipid membrane I: Continuous reversible trajectory from intact bilayer through hydrophobic defect to transversal pore.

Lipid membranes serve as effective barriers allowing cells to maintain internal composition differing from that of extracellular medium. Membrane permeation, both natural and artificial, can take place via appearance of transversal pores. The rearrangements of lipids leading to pore formation in the intact membrane are not yet understood in details.

The Conformation of the Epidermal Growth Factor Receptor Transmembrane Domain Dimer Dynamically Adapts to the Local Membrane Environment.

The epidermal growth factor receptor (EGFR) family is an important class of receptor tyrosine kinases, mediating a variety of cellular responses in normal biological processes and in pathological states of multicellular organisms. Different modes of dimerization of the human EGFR transmembrane domain (TMD) in different membrane mimetics recently prompted us to propose a novel signal transduction mechanism based on protein-lipid interaction. However, the experimental evidence for it was originally obtained with slightly different TMD fragments used in the two different mimetics, compromising the validity of the comparison.

Conformational transitions and interactions underlying the function of membrane embedded receptor protein kinases.

Among membrane receptors, the single-span receptor protein kinases occupy a broad but specific functional niche determined by distinctive features of the underlying transmembrane signaling mechanisms that are briefly overviewed on the basis of some of the most representative examples, followed by a more detailed discussion of several hierarchical levels of organization and interactions involved. All these levels, including single-molecule interactions (e.g.

Helix-helix interactions in membrane domains of bitopic proteins: Specificity and role of lipid environment.

Interaction between transmembrane helices often determines biological activity of membrane proteins. Bitopic proteins, a broad subclass of membrane proteins, form dimers containing two membrane-spanning helices. Some aspects of their structure-function relationship cannot be fully understood without considering the protein-lipid interaction, which can determine the protein conformational ensemble.

Alternative packing of EGFR transmembrane domain suggests that protein-lipid interactions underlie signal conduction across membrane.

The human epidermal growth factor receptor (EGFR) of HER/ErbB receptor tyrosine kinase family mediates a broad spectrum of cellular responses transducing biochemical signals via lateral dimerization in plasma membrane, while inactive receptors can exist in both monomeric and dimeric forms. Recently, the dimeric conformation of the helical single-span transmembrane domains of HER/ErbB employing the relatively polar N-terminal motifs in a fashion permitting proper kinase activation was experimentally determined. Here we describe the EGFR transmembrane domain dimerization via an alternative weakly polar C-terminal motif A(661)xxxG(665) presumably corresponding to the inactive receptor state.

Metabolic Precursor of Cholesterol Causes Formation of Chained Aggregates of Liquid-Ordered Domains.

7-Dehydrocholesterol, an immediate metabolic predecessor of cholesterol, can accumulate in tissues due to some metabolic abnormalities, causing an array of symptoms known as Smith-Lemli-Opitz syndrome. Enrichment of cellular membranes with 7-dehydrocholesterol interferes with normal cell-signaling processes, which involve interaction between rafts and formation of the so-called signaling platforms. In model membranes, cholesterol-based ordered domains usually merge upon contact.

Structure elucidation of dimeric transmembrane domains of bitopic proteins.

The interaction between transmembrane helices is of great interest because it directly determines biological activity of a membrane protein. Either destroying or enhancing such interactions can result in many diseases related to dysfunction of different tissues in human body. One much studied form of membrane proteins known as bitopic protein is a dimer containing two membrane-spanning helices associating laterally.

Modulation of the Bioactive Conformation of Transforming Growth Factor β: Possible Implications of Cation Binding for Biological Function.

In any organism, very precisely adjusted interaction and exchange of information between cellsis continuously required. These cooperative interactions involve numerous cytokines, acting throughcorresponding sets of cell-surface receptors. The transforming growth factor β (TGF-β)superfamily includes a variety of structurally related multifunctional cytokines that play criticalroles in maintaining cellular homeostasis and controlling cell fate.

Unique dimeric structure of BNip3 transmembrane domain suggests membrane permeabilization as a cell death trigger.

BNip3 is a prominent representative of apoptotic Bcl-2 proteins with rather unique properties initiating an atypical programmed cell death pathway resembling both necrosis and apoptosis. Many Bcl-2 family proteins modulate the permeability state of the outer mitochondrial membrane by forming homo- and hetero-oligomers. The structure and dynamics of the homodimeric transmembrane domain of BNip3 were investigated with the aid of solution NMR in lipid bicelles and molecular dynamics energy relaxation in an explicit lipid bilayer.

Two germatranes with bulky substituents.

In 1-adamantyl-2,8,9-trioxa-5-aza-1-germabicyclo[3.3.3]undecane or 1-adamantylgermatrane, [Ge(C(10)H(15))(C(6)H(12)NO(3))], (I), and (2,8,9-trioxa-5-aza-1-germabicyclo[3.

From structure and dynamics of protein L7/L12 to molecular switching in ribosome.

Based on the (1)H-(15)N NMR spectroscopy data, the three-dimensional structure and internal dynamic properties of ribosomal protein L7 from Escherichia coli were derived. The structure of L7 dimer in solution can be described as a set of three distinct domains, tumbling rather independently and linked via flexible hinge regions. The dimeric N-terminal domain (residues 1-32) consists of two antiparallel alpha-alpha-hairpins forming a symmetrical four-helical bundle, whereas the two identical C-terminal domains (residues 52-120) adopt a compact alpha/beta-fold.