What’s in a loop?

Cell Communication and Signaling, Oct 2012

DNAs and proteins are major classes of biomolecules that differ in many aspects. However, a considerable number of their members also share a common architectural feature that enables the assembly of multi-protein complexes and thereby permits the effective processing of signals: loop structures of substantial sizes. Here we briefly review a few representative examples and suggest a functional classification of different types of loop structures. In proteins, these loops occur in protein regions classified as intrinsically disordered. Studying such loops, their binders and their interactions with other loops should reveal much about cellular information computation and signaling network architectures. It is also expected to provide critical information for synthetic biologists and bioengineers.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.biosignaling.com/content/pdf/1478-811X-10-31.pdf

What’s in a loop?

Cell Communication and Signaling Stephan M Feller 0 Marc Lewitzky 0 0 Biological Systems Architecture Group, Weatherall Institute of Molecular Medicine, University of Oxford , Oxford OX3 9DS , UK DNAs and proteins are major classes of biomolecules that differ in many aspects. However, a considerable number of their members also share a common architectural feature that enables the assembly of multi-protein complexes and thereby permits the effective processing of signals: loop structures of substantial sizes. Here we briefly review a few representative examples and suggest a functional classification of different types of loop structures. In proteins, these loops occur in protein regions classified as intrinsically disordered. Studying such loops, their binders and their interactions with other loops should reveal much about cellular information computation and signaling network architectures. It is also expected to provide critical information for synthetic biologists and bioengineers. - To reveal its information, DNA must be untangled and often distant regions within one molecule or between fellow DNA molecules have to interact. These communicating loops enable promoters, enhancers and other regulatory elements, which are sometimes megabases apart, to come together in space and time in a highly dynamic process which is not entirely understood [4,5]. An early example for this type of long-distance interaction was the finding that the beta-globin enhancer, which is located far upstream of the globin genes, comes into close proximity when the genes are actively transcribed [6]. New methodologies, for example the Hi-C method [7-9], are now addressing DNA looping at the whole genome level. Here, protein-DNA complexes at interacting loci are preserved by fixation with formaldehyde, affinity purified and subsequently analyzed by highthroughput sequencing [9]. Apart from their crucial participation in information transfer, DNA loops also play an important role in DNA maintenance. Loop structures at the telomeric ends of chromosomes safeguard and prevent these ends from being treated as DNA double-strand breaks [10]. When the telomeric ends become critically short, loop structures are absent which eventually will result in cell cycle arrest [11]. It goes without saying that loops also play many critical roles in RNA molecules, although they are, to our knowledge, usually not as directly involved in signal processing by protein complex cross-talk. Proteins use loops too, and in a gamut of contexts. Loop regions occur in inter-domain segments of otherwise well-folded proteins, where they can serve multiple functions: short loops sometimes feature as mere linkers or may also provide the required flexibility for the movement of the neighboring protein domains (linker loops [L-L]). Other loops serve as linkers regions, but also allow proteins to interact intramolecularly when undergoing shape changes (intramolecular docking loops [IMD-L]). The linker regions between the SH2s and catalytic domains of Src and Abl kinases [12,13] (and references therein) and the linker region around tyrosine 221, between the SH3 domains of the human c-Crk II protein, are well-studied examples proven to be essential for intramolecular protein binding events [14,15] (and Figure 1). Then there exists a vast number of loop regions which upon modification by specific enzymes serve as docking sites for a single protein interaction partner, or a couple of them (small docking loops [SD-L]). Such loops are found, for example, between the membrane-spanning helices of receptor and channel proteins that reside in cellular membranes. Short loops localized within a well-folded protein domain can also work together to form binding pockets for proteins and a range of other biomolecules (binding pocket loops [BP-L]). In extracellular proteins and polypeptides, functionally vital loop structures, for example generated by disulfide bonds, are found in a vast range of contexts. Classical examples are the loops of the atrial natriuretic peptide hormone family members [32] (and Figure 1). These loops could be designated activity conferring loops [AC-L]. Finally, the human proteome encompasses many proteins suspected to contain much larger loops with numerous putative sites for protein docking [33]. Such larger loops are thought to assemble crucial parts of molecular nanocomputers, which compute signaling input from environment-sensing transmembrane receptors [19,20,33] (and Figure 1). These could be designated as signal computation loops [SC-L]). This type of loops is quite reminiscent of their DNA counterparts, which are, amongst other things, involved in transcriptional regulation. In proteins, they appear preferentially in the anarchic fraction of proteomes; in humans approximately one third of the proteome is thought to consist of partially or mostly unstructured i.e. intrinsically disordered proteins. These fickle and certainly understudied ch (...truncated)


This is a preview of a remote PDF: http://www.biosignaling.com/content/pdf/1478-811X-10-31.pdf

Stephan M Feller, Marc Lewitzky. What’s in a loop?, Cell Communication and Signaling, 2012, pp. 31, 10, DOI: 10.1186/1478-811X-10-31