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.
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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)