The structure and applications of isolated alpha helices

 

A recent minireview in the Journal of Biological Chemistry focuses on the isolated, stable single α-helical, or SAH, domains of proteins.

SAH domains are monomeric, extended α-helices that join globular domains in proteins. They contain a subset of characteristic amino-acid sequences composed of glutamic acid (E) and arginine (R) or lysine (K) called the ER/K motif or ER/K linker. The structural features of SAH domains play important roles in protein function.

In the JBC minireview, authors Carter J. Swanson and Sivaraj Sivaramakrishnan of the University of Michigan review the structure and function of SAH domains and the tools used to identify and predict them. They also discuss the ER/K linker in the context of protein- and cellular-engineering applications.

The minireview introduces the structural conditions that lead to the formation of SAH domains and the differences between SAH domains and coiled-coil motifs. The α-helical structure of SAH domains stems from a combination of the inherent helix-forming tendency of amino acids, such as alanine, and electrostatic interactions between oppositely charged side chains.

The authors discuss studies on the helicity and structural features of synthetic alanine-based helices, such as (EAAAK)n, which laid the foundation for identifying and predicting the stability of isolated α-helices in natural proteins. The unique structural features of the synthetic peptides have useful molecular-engineering applications, such as controlling the bioactivity, expression level and intermolecular spacing of fusion proteins.

Next, the authors highlight techniques used to identify and characterize the SAH domains in natural proteins, such as the smooth muscle caldesmon; human programmed cell death 5 protein, or PDCD5; B. sterthermophilis and others. In each protein, the SAH domain has a specific function. For example, while the SAH domain in smooth muscle caldesmon modulates the actin-myosin interaction, the SAH domain in PDCD5 is purported to play a role in nuclear targeting of PDCD5. Furthermore, bioinformatics analysis of the primary sequences of many other proteins suggests SAH domains may be more prevalent than previously thought. In fact, up to 0.5 percent of all proteins in the human database contain an SAH domain.

The minireview authors also describe studies on the role of mechanical properties of the ER/K motif in myosin function, ER/K linker-based polypeptide sensors for controlling protein–protein interactions, and modulation of the protein interactions and enzymatic activity of focal adhesion kinase. 

The authors conclude that the ubiquity and modular nature of the ER/K motifs make them versatile tools for manipulating proteins and understanding their roles within cellular systems. Furthermore, they suggest, the ER/K-based sensor platforms have direct implications for identifying small-molecule therapeutics.

Indumathi SridharanIndumathi Sridharan (sridharan.indumathi@gmail.com) earned her bachelor’s degree in bioinformatics in India. She holds a Ph.D. in molecular biochemistry from Illinois Institute of Technology, Chicago.
She did her postdoctoral work in bionanotechnology at Northwestern University.