News & Views in 2001

Ion channel proteins provide a pathway for movement of ions across the hostile, low-dielectric environment of the membrane. New work on crystalline bacterial K⁺ channels shows that this process is optimized for the natural substrate, K⁺. An additional high resolution structure of the channel illustrates how the protein provides prosthetic solvation for the ion — and also a beautiful picture of how water itself solvates the ion.

After reconstitution into liposomes, Tim23p, a mitochondrial inner membrane protein required for protein import, forms an aqueous pore that is activated by a transmembrane potential and mitochondrial targeting peptides. A report in this issue suggests that proteins are translocated into the mitochondrial matrix through a channel formed by Tim23p. These data also suggest a mechanism by which protein import can occur without disrupting the permeablility barrier of the inner membrane.

The structures of four type III secretion chaperones provide insights into how they function in the translocation process.

A powerful new NMR technique applied to the ubiquitous Ca²⁺ sensor, calmodulin, reveals significant conformational flexibility within each globular domain, which contributes to its ability to bind a wide range of targets. These measurements of residual dipolar couplings between nuclear spins demonstrate a fast and accurate method for pinpointing structural features that cannot be delineated reliably by traditional NOE analysis.

The 4.5 Å map of the MsbA protein, a putative lipid A transporter from Escherichia coli, provides the first detailed structural model for the transmembrane domain and cytoplasmic 'loops' of an ABC transporter and the geometric relationship of these regions to the ATP-binding cassette motor domain. Based on this structure, specific hypotheses for the mechanics of the pump can now be formulated and tested.

In the absence of other biological information, the detection of remote homology is a prerequisite step toward understanding the function of a new protein. A novel method based on structure comparison improves our ability to do this automatically and systematically.

Structural characterization of a variety of DNA polymerases has likened the polymerase domain to a hand that grasps DNA with functional subdomains referred to as fingers, palm and thumb. The solution structure of the African swine fever virus DNA polymerase X indicates that it does not have a hand-like architecture and suggests a mechanism by which the polymerase may compensate for the lack of a dedicated DNA binding subdomain.

Many proteins frequently undergo structural rearrangement to complete their functions. Ligand entry and binding are often associated with some degree of localized disorder. Indeed, low populations of disordered excited states may help drive such processes. Characterization of these states is vital to understanding the mechanisms of many biological functions.

Structures of two regions of BRCA1 offer important insights into the molecular properties of this tumor suppressor.

Death-associated protein kinase (DAP-kinase; DAPk) has been implicated in programmed cell death and tumor suppression. The recently solved crystal structure of the catalytic domain of human DAP-kinase reveals interesting 'fingerprint' regions that may be functionally important.

Recent crystal structures of error prone DNA polymerases that bypass damage in DNA templates provide counterexamples to high fidelity polymerases.

Crystal structures of the Escherichia coli DNA replication γ clamp loading complex and of a subunit of the clamp loader bound to a β clamp monomer provide a physical framework in which to view ATP-dependent modulation of γ complex–β interactions. The structural data suggest how the β ring is opened and loaded onto DNA in the absence of a direct interaction between the γ complex and the β dimer interface.

Copper is an essential transition metal that plays a fundamental role in the biochemistry of all aerobic organisms. Recent work elucidating the structural mechanisms of copper delivery to superoxide dismutase provides insight into the cell biology of copper metabolism and serves as an example of how to understand the principles governing the incorporation of metals into proteins.

The first crystal structure of an actin molecule not associated with another protein has been solved. Remarkably, the most variable part of actin's structure is also the most conserved part of its sequence.

Unambiguous evidence for a glycosyl-enzyme intermediate on the lysozyme reaction pathway has recently been reported, finally settling what kind of mechanism this textbook enzyme uses.

A recent study of cytomegalovirus assemblin proteinase suggests that dimer-induced stabilization of the oxyanion hole may activate the enzyme.

NMR analyses of variants of the p53 tumor suppressor protein that either contain or lack the C-terminus reveal that the C-terminus neither interacts with other regions of p53 nor has an impact on the conformation of the rest of the molecule. Nevertheless, the C-terminus is likely to be critical for regulation of p53 function.

NMR experiments with partially aligned protein molecules in strongly denaturing conditions suggest that the unfolded state is less chaotic than is widely believed. Hence protein folding is probably less paradoxical than Levinthal originally thought.

DNA polymerases play a central role in maintenance of genetic information, and the structures of polymerases in complex with DNA and dNTP provide valuable insights into mechanisms utilized by DNA polymerases to achieve high fidelity. Comparison of several high resolution complexes of DNA polymerases bound with relevant substrates indicates that the two major families of polymerases function by very similar mechanisms.

Recent crystal structures suggest models for how an asymmetric E2/E2-like protein complex synthesizes a polyubiquitin chain that functions in DNA repair and NF-κB activation pathways.