Nanomaterials (NMs) have gained prominence in technological advancements due to their tunable physical, chemical and biological properties with enhanced performance over their bulk counterparts. NMs are categorized depending on their size, composition, shape, and origin. The ability to predict the unique properties of NMs increases the value of each classification. Due to increased growth of production of NMs and their industrial applications, issues relating to toxicity are inevitable. The aim of this review is to compare synthetic (engineered) and naturally occurring nanoparticles (NPs) and nanostructured materials (NSMs) to identify their nanoscale properties and to define the specific knowledge gaps related to the risk assessment of NPs and NSMs in the environment. The review presents an overview of the history and classifications of NMs and gives an overview of the various sources of NPs and NSMs, from natural to synthetic, and their toxic effects towards mammalian cells and tissue. Additionally, the types of toxic reactions associated with NPs and NSMs and the regulations implemented by different countries to reduce the associated risks are also discussed.

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Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations.

Summary: ATP-binding cassette (ABC) systems are universally distributed among living organisms and function in many different aspects of bacterial physiology. ABC transporters are best known for their role in the import of essential nutrients and the export of toxic molecules, but they can also mediate the transport of many other physiological substrates. In a classical transport reaction, two highly conserved ATP-binding domains or subunits couple the binding/hydrolysis of ATP to the translocation of particular substrates across the membrane, through interactions with membrane-spanning domains of the transporter. Variations on this basic theme involve soluble ABC ATP-binding proteins that couple ATP hydrolysis to nontransport processes, such as DNA repair and gene expression regulation. Insights into the structure, function, and mechanism of action of bacterial ABC proteins are reported, based on phylogenetic comparisons as well as classic biochemical and genetic approaches. The availability of an increasing number of high-resolution structures has provided a valuable framework for interpretation of recent studies, and realistic models have been proposed to explain how these fascinating molecular machines use complex dynamic processes to fulfill their numerous biological functions. These advances are also important for elucidating the mechanism of action of eukaryotic ABC proteins, because functional defects in many of them are responsible for severe human inherited diseases.

Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems

Helicases and translocases are a ubiquitous, highly diverse group of proteins that perform an extraordinary variety of functions in cells. Consequently, this review sets out to define a nomenclature for these enzymes based on current knowledge of sequence, structure, and mechanism. Using previous definitions of helicase families as a basis, we delineate six superfamilies of enzymes, with examples of crystal structures where available, and discuss these structures in the context of biochemical data to outline our present understanding of helicase and translocase activity. As a result, each superfamily is subdivided, where appropriate, on the basis of mechanistic understanding, which we hope will provide a framework for classification of new superfamily members as they are discovered and characterized.

Structure and mechanism of helicases and nucleic acid translocases.

A decisive step in the biosynthesis of many proteins is their partial or complete translocation across the eukaryotic endoplasmic reticulum membrane or the prokaryotic plasma membrane. Most of these proteins are translocated through a protein-conducting channel that is formed by a conserved, heterotrimeric membrane-protein complex, the Sec61 or SecY complex. Depending on channel binding partners, polypeptides are moved by different mechanisms: the polypeptide chain is transferred directly into the channel by the translating ribosome, a ratcheting mechanism is used by the endoplasmic reticulum chaperone BiP, and a pushing mechanism is used by the bacterial ATPase SecA. Structural, genetic and biochemical data show how the channel opens across the membrane, releases hydrophobic segments of membrane proteins laterally into lipid, and maintains the membrane barrier for small molecules.

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Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes

The DEAD-box protein family of RNA helicases

The conserved protein-conducting channel, referred to as the Sec61 channel in eukaryotes or the SecY channel in eubacteria and archaea, translocates proteins across cellular membranes and integrates proteins containing hydrophobic transmembrane segments into lipid bilayers. Structural studies illustrate how the protein-conducting channel accomplishes these tasks. Three different mechanisms, each requiring a different set of channel binding partners, are employed to move polypeptide substrates: The ribosome feeds the polypeptide chain directly into the channel, a ratcheting mechanism is used by the eukaryotic endoplasmic reticulum chaperone BiP, and a pushing mechanism is utilized by the bacterial ATPase SecA. We review these translocation mechanisms, relating biochemical and genetic observations to the structures of the protein-conducting channel and its binding partners.

Protein translocation by the Sec61/SecY channel.

Protein translocation is mediated by oligomers of the SecY complex with one SecY copy forming the channel.

The ATPase SecA mediates the posttranslational translocation of a wide range of polypeptide substrates through the SecY channel in the cytoplasmic membrane of bacteria. We have determined the crystal structure of a monomeric form of Bacillus subtilis SecA at a 2.2-A resolution. A comparison with the previously determined structures of SecA reveals a nucleotide-independent, large conformational change that opens a deep groove similar to that in other proteins that interact with diverse polypeptides. We propose that the open form of SecA represents an activated state.

A large conformational change of the translocation ATPase SecA

An important step in the biosynthesis of many proteins is their partial or complete translocation across the plasma membrane in prokaryotes or the endoplasmic reticulum membrane in eukaryotes. In bacteria, secretory proteins are generally translocated after completion of their synthesis by the interaction of the cytoplasmic ATPase SecA and a protein-conducting channel formed by the SecY complex. How SecA moves substrates through the SecY channel is unclear. However, a recent structure of a SecA-SecY complex raises the possibility that the polypeptide chain is moved by a two-helix finger domain of SecA that is inserted into the cytoplasmic opening of the SecY channel. Here we have used disulphide-bridge crosslinking to show that the loop at the tip of the two-helix finger of Escherichia coli SecA interacts with a polypeptide chain right at the entrance into the SecY pore. Mutagenesis demonstrates that a tyrosine in the loop is particularly important for translocation, but can be replaced by some other bulky, hydrophobic residues. We propose that the two-helix finger of SecA moves a polypeptide chain into the SecY channel with the tyrosine providing the major contact with the substrate, a mechanism analogous to that suggested for hexameric, protein-translocating ATPases.

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Andrew R. Osborne

Papers

Protein translocation by the Sec61/SecY channel.

Protein translocation is mediated by oligomers of the SecY complex with one SecY copy forming the channel.

A large conformational change of the translocation ATPase SecA

A large conformational change of the translocation ATPase SecA

A role for the two-helix finger of the SecA ATPase in protein translocation